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Four Ways to Show Nonobviousness of ADC Inventions

When the first antibody-drug conjugate (ADC) was approved by the U.S. Food and Drug Administration (FDA) in 2000,[1] only a handful of patent applications claiming ADCs had been published.[2] As research continues to progress and the scientific community’s appreciation for the power of ADCs has grown, so have the numbers. FDA has now approved at least four ADCs,[3] and hundreds more are in development.[4] The number of patent applications has also grown, with the U.S. Patent and Trademark Office (USPTO) publishing over two hundred patent applications with claims to ADC inventions in the last two years alone.[5]

But filing an application with the USPTO does not guarantee that a patent will be obtained. Among other requirements, inventions worthy of U.S. patent protection must not have been obvious to a person of ordinary skill in the art at the time of invention (or, under current U.S. patent law, at the time the patent application was filed). In considering whether an invention would have been obvious, the USPTO will consider what was already known in the art, how the claimed invention differs from what was already known, and whether the differences would have been obvious. An invention may be deemed nonobvious if, for example, there was no motivation to modify what was known or no reasonable expectation of success in achieving the claimed invention, or if the invention enjoys commercial success or demonstrates results that would have been unexpected at the time of invention.

Four ways to demonstrate nonobviousness of an ADC invention are to show that (1) the claimed antibody, drug, or linker was not previously known; (2) a person having ordinary skill in the art would not have been motivated to modify known components to achieve the claimed ADC; (3) the skilled artisan would have had no reasonable expectation of success; or (4) the claimed ADC demonstrates unexpected results. These types of arguments have been presented to the USPTO in ADC-based patent applications, often in combination with each other and with amendments to the pending claims.

Provided below are three examples of patents that issued after such nonobviousness arguments were made to the USPTO: U.S. Patent Nos. 8,603,483 (the ’483 patent); 9,308,278 (the ’278 patent); and 9,850,312 (the ’312 patent). Companies seeking patent protection for their own ADC inventions should consider these and other examples when developing their own nonobviousness positions. The authors have not independently analyzed the obviousness of the claims discussed below, but provide these merely as examples of strategies used to secure allowance of claims directed to ADCs before the USPTO. Readers are encouraged to seek legal counsel in considering their own ADC inventions and these examples.


Example 1: Arguments of No Motivation, No Reasonable Expectation of Success, and Unexpected Results During the Prosecution of U.S. Patent No. 8,603,483 [6]

The USPTO issued the ’483 patent to Janssen Biotech, Inc. and ImmunoGen, Inc. on December 10, 2013, with claims to ADCs, pharmaceutical compositions comprising the ADCs, articles of manufacture comprising the ADCs, methods of producing the ADCs, methods of treating cancer using the ADCs, and methods of inhibiting the growth of cancer cells using the ADCs. For example, independent claim 1 is as follows:

1. An antibody-drug conjugate of the formula:

wherein the antibody is a human alphaV integrin specific antibody, and said antibody is capable of being internalized by a cell expressing said alphaV integrin, and wherein said antibody comprises (i) all of the heavy chain complementary determining region (CDR) amino acid sequences of CNTO 95 as shown in SEQ ID NOS: 1, 2, and 3, and (ii) all of the light chain CDR amino acid sequences of CNTO 95 as shown in SEQ ID NOS: 4, 5, and 6; and wherein the maytansinol is esterified at C-3; R1 and R2 are Me; X1 and X2 are H[;] n is 2; p is 2; and m is 3-4, and the pharmaceutically acceptable salts and esters thereof.

On June 3, 2011, during prosecution of the application that issued as the ’483 patent, the USPTO examiner rejected the then-pending claims for obviousness over combinations of four references. According to the examiner, the first reference taught an immunoconjugate comprising the antibody of CNTO 95 linked to a cytotoxin, the second reference taught that blockade of integrin receptors by CNTO 95 inhibited the growth of new blood vessels in vitro and growth of human melanoma tumors in nude mice, and the third reference taught that CNTO 95 has antitumor and antiangiogenic activity in vivo.

The examiner wrote that the invention of the then-pending claims differed from these teachings only by the recitation that the conjugate has the formula of [C‑L]m‑A, wherein C is DM4 (R1 and R2 are Me and n=2). According to the examiner, the fourth reference taught a conjugate comprising the huMy9-6 monoclonal antibody chemically coupled to maytansinoid DM4 via an N-succinimidyl 4-(2-yridyldithio)butanoate, and it would have been obvious to one of ordinary skill in the art to substitute hyMy9-6 antibody with the CNTO-95 antibody.

In a response dated December 2, 2011, the applicant amended the claims and argued that one of skill in the art at the time of invention would not have been motivated to substitute the CNTO 95 antibody for the huMy9-6 monoclonal because the two antibodies are “very different.” The applicant also argued that an artisan would not have reasonably expected success in substituting one antibody with another antibody that is structurally and chemically very different. In addition, the applicant argued that the art did not suggest that conjugating an anti-alphaV antibody to a cytotoxic drug would provide an important improvement or advantage over the use of the unconjugated CNTO 95 antibody. In support of the arguments, the applicant submitted three declarations. In the first, a named inventor declared that the effectiveness of the CNTO 95-maytansinoid conjugate CNTO 365 in treating tumors was surprising. In the second, a scientist declared that an artisan would not have been motivated to substitute huMy9-6, a highly selective antibody, with CNTO 95, an antibody with high reactivity with normal tissue, and would not have had a reasonable expectation of success. In the third, another scientist provided results from a phase I clinical study using CNTO 365, which the applicant argued showed unexpected and surprisingly low toxicity.

On January 12, 2012, the USPTO examiner maintained the obviousness rejections of the then-pending claims over the same art. The examiner wrote that while CNTO 95 was unexpectedly well tolerated in human clinical trials, the unexpected results did not overcome clear and convincing evidence of obviousness.

In a response dated September 12, 2012, the applicant amended the claims to “closely encompass the CNTO 365 conjugate described and tested in the application,” and argued that the claimed conjugates demonstrated unexpected results because they had a more than four-fold lower EC50 in toxicity studies relative to even other CNTO 95 conjugates. The USPTO examiner issued a notice of allowance, and then the ’483 patent issued on December 10, 2013. The examiner wrote that the amended claims were allowed because CNTO 365 was shown to have superior efficacy.


Example 2: Arguments of No Motivation and Unexpected Results During the Prosecution of U.S. Patent No. 9,308,278 [7]

The USPTO issued the ’278 patent to Agensys, Inc. on April 12, 2016, with claims to ADCs and pharmaceutical compositions comprising the ADCs. For example, independent claim 1 is as follows:

1. An antibody drug conjugate obtained by a process comprising the step of:

conjugating an antibody or antigen binding fragment thereof to monomethyl auristatin F (MMAF), which antibody or antigen binding fragment thereof is expressed by a host cell comprising a nucleic acid sequence encoding an amino acid sequence of a VH region consisting of SEQ ID NO:7, from residues 20 to 142, and a nucleic acid sequence encoding an amino acid sequence of a VL region consisting of SEQ ID NO:8, from residues 20 to 127, thereby producing the antibody drug conjugate.


On July 2, 2015, the USPTO examiner rejected the then-pending claims for obviousness over combinations of five references. According to the examiner, four of the references taught cancer immunotherapy using anti-161P2F10B antibodies such as H16-7.8 conjugated to auristatins such as monomethyl auristatin E (MMAE) for use in treating cancer, and the fifth reference taught that MMAF is an antimitotic auristatin derivative with a charged C-terminal phenylalanine residue that attenuates its cytotoxic activity compared to its uncharged counterpart, MMAE. The examiner wrote that an artisan would have been motivated to replace MMAE with MMAF based on the fifth reference’s showing of improved therapeutic effects.

In a response dated September 23, 2015, the applicant argued that the first four references would not have motivated an artisan to conjugate the H16-7.8 antibody with MMAF or to target cells expressing 161P2F10B protein with the claimed ADC because the references broadly disclosed more than twenty different monoclonal antibodies and more than fifty different cytotoxic agents, not one of which was MMAF. The applicant also argued that the claimed ADC comprising the claimed H16-7.8 antibody conjugated to MMAF produced surprising results. In support of this argument, the applicant relied on data showing that the H16-7.8 MMAF conjugate inhibited tumor growth for sixty days, a result not obtained with either the H16-1.11 MMAF conjugate or the H16-7.8 MMAE conjugate. The USPTO withdrew the obviousness rejections, and then the ’278 patent issued on April 12, 2016. The examiner wrote that the applicant’s argument of unexpected results was persuasive.


Example 3: Arguments of New Components, No Motivation, and No Reasonable Expectation of Success During the Prosecution of U.S. Patent No. 9,850,312 [8]

The USPTO issued the ’312 patent to Daiichi Sankyo Company, Limited and Sapporo Medical University on December 26, 2017, with claims to ADCs, pharmaceutical compositions comprising the ADCs, antitumor drugs and anticancer drugs containing the ADCs, and methods of treating cancer using the ADCs. For example, independent claim 1 is as follows:

1. An antibody-drug conjugate, wherein a linker and an antitumor compound represented by the following formula and anti-TROP2 antibody are connected:

-(Succinimid-3-yl-N)—CH2CH2CH2CH2CH2—C(=O)-GGFG-NH—CH2—O—CH2—C(=O)—(NH-DX) . . .

wherein the anti-TROP2 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 23, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 24 and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 25 in its heavy chain variable region and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 26, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 27 and CDRL3 consisting of the amino acid sequence of SEQ ID NO:28 in its light chain variable region.


On October 21, 2016, the USPTO examiner rejected the then-pending claims for obviousness over three references. According to the examiner, the first reference taught drug delivery systems in which exatecan is linked to a GGFG tetrapeptide, but not the ADC with anti-TROP2 antibody and the linkers in the then-pending claims. The examiner wrote that the second reference taught ADCs using maleimidocaproyl attached to an amino acid spacer attached to a maytansinoid drug moiety, and that the third reference taught ADCs having the anti-TROP2 antibody hRS7 with a drug. The examiner wrote that it would have been obvious to prepare the ADC using the first reference’s exatecan linked to a GGFG tetrapeptide composition with the maleimidocaproyl of the second reference and the anti-TROP2 antibody of the third reference.

In a response dated January 18, 2017, the applicant amended the claims and argued that the claimed ADC comprised a novel linker having a specific structure and a novel anti-TROP2 antibody. The applicant argued that even if exatecan was known in the art, its ability to maintain and exert antitumor activity in the claimed structure was “a totally new finding” and there was no expectation of success. The applicant also argued that the only cited reference that disclosed an anti-TROP2 antibody did not disclose one with the claimed CDR sequences. The applicant argued that the references did not teach or suggest the claimed antibody or provide the necessary motivation to arrive at the claimed antibody with a reasonable expectation of success. The examiner issued a notice of allowance, and then the ’302 patent issued on December 26, 2017.

Conclusion
Companies developing ADCs should strategically obtain patent protection for their products, keeping in mind that their ability to have a patent granted may hinge on the success of their arguments of nonobviousness of the invention. As seen from the examples above, applicants often use a combination of arguments and claim amendments when responding to an obviousness rejection. By considering how other companies have responded to obviousness rejections by the USPTO, companies can gain insight into how to obtain and preserve patent protection for their own ADC inventions.


How to cite:
Eaton J, Miller P, Cyr SK. Four Ways to Show Nonobviousness of ADC Inventions (2018),
DOI: 10.14229/jadc.2018.10.05.001.


Original manuscript received: August 25, 2018 | Manuscript accepted for Publication: August 21, 2018 | Published online September 27, 2018 | DOI: 10.14229/jadc.2018.10.05.001.

Last Editorial Review: October 5, 2018

Featured Image: Patent Concept button. Courtesy: © Fotolia. Used with permission.

Creative Commons License

This work is published by InPress Media Group, LLC (Four Ways to Show Nonobviousness of ADC Inventions) and is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Non-commercial uses of the work are permitted without any further permission from InPress Media Group, LLC, provided the work is properly attributed. Permissions beyond the scope of this license may be available at adcreview.com/about-us/permission.


Copyright © 2010 – 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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ADCs – The Dawn of a New Era?

The technology behind antibody-drug conjugates (ADCs) has been around for many years, but so far is without widespread commercial success. Penelope Drake and David Rabuka of Catalent Biologics assess the history and progress to date, and look at what might be preventing ADCs from reaching their full potential.


Abstract
Two decades ago, antibody-drug conjugates or ADCs were hailed as a major breakthrough, especially in the area of oncology therapeutics. The concept of delivering a potent drug payload directly to the site of the tumor for maximum effect with minimal damage caused to non-cancerous cells was viewed as, if not the Holy Grail of cancer treatment, at least a significant advance towards precision medicine. However, the concept has proved difficult to translate into clinical success.

1.0: Introduction
The first ADC reached the market in 2000, but to date, the U.S. Food and drug Administration (FDA) has approved only four ADC therapeutics. The two most recent were granted approval in 2017, and could mark the start of a new era in which ADCs begin to realize their full potential.

The two drugs approved most recently by the FDA are inotuzumab ozogamicin (Besponsa®) and gemtuzumab ozogamicin (Mylotarg®). Mylotarg, the very first marketed ADC, was originally approved in 2000 for treatment of CD33-positive acute myeloid leukemia (AML).

However, treatment-related toxicity concerns led to its withdrawal from the market in 2010, but it has now been re-approved with a lower recommended dose and altered dosing schedule.

Besponsa was approved for treatment of relapsed/refractory acute lymphoblastic leukemia (ALL).[1,2] They join brentuximab vedotin (Adcetris®), an anti-CD30 monomethyl auristatin E (MMAE) conjugate approved in 2011 to treat relapsed/refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, and ado-trastuzumab emtansine (Kadcyla®), an anti-HER2 DM1 conjugate approved in 2013 to treat HER2+ metastatic breast cancer. Kadcyla is currently the only FDA-approved ADC for the treatment of solid tumors.

2.0: An Hybrid Entity
An ADC is very much a hybrid entity, combining both biologic and small molecule characteristics, and consisting of an antibody scaffold covalently modified with a variable number of small-molecule payloads, joined by a chemical linker. The antibody delivers the small molecule specifically to the intended cell type by targeting an antigen that is selectively expressed on tumor cells and internalizes upon antibody engagement. To be an effective therapy, all of these parts of the ADC must be optimized.

Changes to the linker can have a significant effect on the biophysical and functional performance of the ADC, and there are two main conjugation approaches for attaching linkers to antibodies, resulting in either heterogeneous or site-specific payload placement. Currently, the ADC clinical pipeline is still dominated by heterogeneous conjugates, although the functional and analytical advantages of site-specific conjugation [3] are now being recognized.

The average ratio of conjugated payload to antibody is referred to as the drug-to-antibody ratio (DAR) and this has a strong influence on both the efficacy and toxicity of an ADC. High-DAR ADCs can have poor biophysical characteristics that reduce efficacy and increase toxicity, but these effects can be mitigated using certain conjugation and linker technologies.[3]

3.0 Clinically-tested Payloads
To date, the majority of clinically-tested ADC payloads are either antimitotic/microtubule inhibiting, such as auristatins, maytansinoids and tubulysin, or DNA alkylating (e.g., pyrrolobenzodiazepines, indolinobenzodiazepines, calicheamicins, duocarmycins), although a few other interesting payloads with novel mechanisms of action have been introduced (irinotecan derivatives and α-amanitin).

The past five years however, have seen a dramatic change in the ADC clinical pipeline as preclinical technological advances have started to feed into clinical-stage projects. In early 2013, of the 20 ADCs in the clinic, nearly 80% were heterogeneous conjugates with payloads of antimitotic drugs, namely auristatins or maytansinoids. But between 2013 and 2017, the number of ADCs in clinical trials more than tripled [4], with site-specific ADCs accounting for nearly 15% of the total. There has also been a trend away from antimitotic payloads towards more potent cytotoxic drugs, particularly DNA alkylators.

The proportion of antimitotic payloads fell from 80% to 65% overall, and accounted for only one-third of site-specific ADCs. This decline can be attributed in part to the unimpressive clinical results of ADCs bearing antimitotic payloads.

According to a recent review [4], nearly 40% of ADCs bearing maytansine, monomethyl auristatin E (MMAE), or monomethyl auristatin F (MMAF) that entered clinical trials were later discontinued, presumably due to lack of efficacy or (rarely) excessive toxicity.

However, the highly potent DNA alkylating payloads carry an increased risk to patients and the fine line between potency and safety is one that scientists and regulators are still striving to achieve. The first site-specific ADC to reach the clinic, vadastuximab talirine, is an anti-CD33 antibody conjugated through engineered cysteine residues in the heavy chain to yield a DAR 2 molecule and is the first clinical ADC to bear a pyrrolobenzodiazepine (PBD) payload, a highly potent DNA alkylator.

It began clinical phase 1 trials in mid-2013, but the phase 3 trial was recently terminated due to toxicity concerns[5], even though the drug showed a 70% complete remission rate for AML patients.[6]

4.0: Mechanisms of toxicity
Meaningful improvements in ADC technology are expected to continue as preclinical studies focus on understanding the mechanisms of ADC toxicity, developing approaches for reducing off-target toxicities, and improving patient outcomes through changes in both ADC composition and clinical trial study design.

As yet, most clinical experience has been with ADCs carrying antimitotic payloads, which show prominent organ toxicities in the hematopoietic compartments and in the liver. Much less is known about the clinical effects of dosing DNA alkylators, although targeting of the hematopoietic compartments has been shown in clinical trials.

A deeper understanding is needed of the absorption, distribution, metabolism, and excretion (ADME) and drug metabolism and pharmacokinetics (DMPK) fates of both the intact conjugate and its small molecule component. Knowing where the drug goes and how it is processed will enable connections to be drawn with commonly observed clinical toxicities.

A 2015 review of toxicity studies [7] concluded that ADC toxicity was not driven by target antigen but rather by linker/payload: ADCs sharing the same linker/payload composition tended to reach the same maximum tolerated dose, even when their target antigens showed endogenous expression in completely different tissue/organ compartments.

This sobering observation revealed how much progress still needs to be made to achieve specific cytotoxic payload delivery to tumor cells without damaging healthy tissues. But it also offers a possible explanation for the high failure rate of 2013 era ADCs.

It is likely that the lack of clinical benefit observed for some ADCs was the result of an inability to dose to an efficacious level due to off-target toxicities driven by the linker/payload.

If ADC off-target toxicity can be controlled, then it is likely that the maximum tolerated dose can be increased, perhaps leading to better clinical response to treatment.


How to cite:
Drake P, Rabuka D, ADCs – The Dawn of a New Era? (2018),
DOI: 10.14229/jadc.2018.08.27.001.


Original manuscript received: July 25, 2018 | Manuscript accepted for Publication: August 21, 2018 | Published online August 27, 2018 | DOI: 10.14229/jadc.2018.08.27.001.

Last Editorial Review: August 25, 2018

Featured Image: Medical research | Microscope. Courtesy: © Fotolia. Used with permission.

Creative Commons License

This work is published by InPress Media Group, LLC (ADCs – The Dawn of a New Era?) and is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Non-commercial uses of the work are permitted without any further permission from InPress Media Group, LLC, provided the work is properly attributed. Permissions beyond the scope of this license may be available at adcreview.com/about-us/permission.


Copyright © 2010 – 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Antibody-Drug Conjugates at the 59th American Society of Hematology Annual Meeting

This year, in Atlanta, the South’s largest and most vibrant city, the 59th annual meeting and exposition of the American Society of Hematology, to be held December 9-12, 2017, is expected to bring an invaluable educational experience and the opportunity to review thousands of scientific abstracts highlighting updates in the hottest topics in hematology.

The world’s most comprehensive hematology event of the year will provide an opportunity to Network with top minds in the field and a global community of more than 25,000 hematology professionals from every subspecialty.

New developments in antibody-drug conjugates are expected to create excitement.

Changing landscape
The landscape of antibody-drug conjugates is rapidly changing. [1]

In January 2017 only two ADCs were commercially available in the United States.  This included brentuximab vedotin (Adcetris®; Seattle Genetics), an anti-CD30 monomethyl auristatin E (MMAE) conjugate indicated for the treatment of patients with relapsed/refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, and ado-trastuzumab emtansine (also know as T-DM1; Kadcyla®; Genentech/Roche), an anti-HER2 DM1 conjugate used to treat HER2-metastatic breast cancer. a


For an overview of oral and poster presentations about antibody-drug conjugates (ADCs) to be presented during the annual meeting of the American Society of Hematology, December 9 – 12, 2017, Click here.


Then in the late summer of this year the number of commercially available antibody-drug conjugates approved by the U.S. Food and Drug Administration (FDA) doubles with the approval, inotuzumab ozogamicin (Besponsa®; Pfizer) for treatment of relapsed/refractory acute lymphoblastic leukemia (ALL) and gemtuzumab ozogamicin (Mylotarg®; Pfizer) b, for relapsed/refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma.

With four commercially available antibody-drug conjugates, the majority of which are for the treatment of liquid cancers, and with a better understanding of cancer biology and many technological advances, this class of novel (anti-cancer) agents is finally beginning to deliver on decades old expectations and hope for better therapeutic outcomes.

But some of the hope and expectation are still ‘locked’ in early and preclinical research, as is evidenced by the fact there are more than 150 ADC and ADC-like agents in development programs.

Penelope Drake and David Rabuka, in a recent article published in BioDrugs, discuss how our better understanding and advances are based upon a large – and increasing – body of investigational studies which, taken together, offer a deeper knowledge and comprehension of the absorption, distribution, metabolism, and excretion (ADME), drug metabolism and pharmacokinetics (DMPK) fates of the intact conjugate and its small-molecule drug component.[1]

This year, during the annual meeting of the American Society of Hematology a number of  companies will again present their latest developments.

IMGN632 and IMGN779
ImmunoGen, will highlight two experimental ADC therapies, IMGN632 and IMGN779, a CD33-targeted ADC for the treatment of acute myeloid leukemia or Acute Myeloid Leukemia currently in Phase I testing.

Both IMGN779 and IMGN632 use ImmunoGen’s novel indolino-benzodiazepine payloads called IGNs. These ultra-potent, DNA-acting IGNs alkylate DNA without crosslinking, which preclinically has resulted in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.

Acute Myeloid Leukemia is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems and anemia.

It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients are expected to die from the disease [2]

IMGN632 is a humanized anti-CD123 antibody-drug conjugate that is a potential treatment for for hematological malignancies, including AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN), myelodysplastic syndrome, B-cell acute lymphocytic leukemia, and other CD123-positive malignancies.

Earlier this year, ImmungGen announced that the Investigational New Drug application for IMGN632 is active and it expects to open a Phase I trial later this year.

IMGN779 is a novel ADC that combines a high-affinity, humanized anti-CD33 antibody, a cleavable disulfide linker, and one of ImmunoGen’s novel indolino-benzodiazepine payloads, called IGNs, which alkylate DNA without crosslinking, resulting in potent preclinical anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.

IMGN779 is in Phase I clinical testing for the treatment of AML.

“The clinical and preclinical data to be presented at ASH demonstrate the early potential of our novel IGN portfolio,” said Richard Gregory, Ph.D., executive vice president and chief scientific officer of ImmunoGen.

“One of our strategic priorities is to accelerate the development of these unique and highly differentiated assets. IMGN779 and IMGN632 use our IGN payloads, which were designed to meet the dual challenges of achieving high potency against target cells, while having a tolerability profile that enables continued patient treatment,” Gregory added.

In a poster presentation, the ImmunoGen is expected to report updated data evaluating the safety and anti-leukemia activity from the dose escalation phase of the IMGN779 first-in-human trial. In a separate presentation, preclinical data evaluating the mechanism, anti-leukemia efficacy, and tolerability of repeated dosing of IMGN779 and cytarabine in combination using in vitro and in vivo human AML preclinical models will be reported.

Preclinical data reporting the prevalence of CD123 expression in acute lymphoblastic leukemia (ALL), and assessing the anti-leukemia activity of IMGN632 on ALL cells will be presented in a poster presentation.

Novel payloads: Antibody-targeted Amanitin conjugates
Today, most antibody-drug conjugates, both commercially available and in clinical trials, includes just a limited number of cytotoxic payloads, generally limited to microtubuli- or DNA-targeting toxins including auristatins and maytansines or duocarmycins and pyrrolobenzodiazepines (PBDs). These payloads are mainly targeting proliferating cells potentially leading to limited efficacy in diseases with a low proliferation rates such as indolent lymphomas or multiple myeloma.

Researchers at the German Cancer Research Center, Heidelberg, Baden-Württemberg, Germany in collaboration with Heleidelberg Pharma are developing a novel antibody-drug conjugate with amanitin as toxic payload with an alternative toxicity mechanisms that could enhance the therapeutic potential of ADCs.

Amanitin is the most well-known toxin of the amatoxin family and binds to the eukaryotic RNA polymerase II, inhibiting the cellular transcription process at very low concentrations irrespective of the proliferation status of the target cell.

During this year’s annual meeting, researchers from the German Cancer Research Center will present results of a study assessing in vitro and in vivo specificity and efficacy of HDP-101, an ATAC targeting BCMA (B cell maturation anti­gen; CD269), which is expressed on cells of the B cell lineage, predominantly on plasma blasts and plasma cells. BCMA is highly expressed on malignant plasma cells and therefore considered an ideal target in multiple myeloma, is not expressed on naïve, germinal center, and memory B cells.

The researchers conclude that the mode of action of the amanitin payload led to an efficient anti-tumor response in vitro and in vivo with good tolerability in non-human primate studies yielding a very favorable therapeutic index.

A first-in-human trial with HDP-101 as a potential treatment for multiple myeloma is expected to start in 2018.

Brentuximab vedotin
This year 18 abstracts will featuring data from the broad brentuximab vedotin (Adcetris®; Seattle Genetics) development program. Brentuximab vedotin, an ADC directed to CD30, which is expressed on the surface of Hodgkin lymphoma cells and several types of non-Hodgkin lymphoma, is being evaluated globally as the foundation of care for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials.

The presentations during this years annual meeting include data from the phase III ECHELON-1 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in frontline advanced classical Hodgkin lymphoma patients.

Based on the positive results from the ECHELON-1 trial, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to ADCETRIS in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma.

During the annual meeting numerous oral and poster presentations will highlight additional progress within the brentuximab vedotin development program including:

  • Updated durability results from the phase III ALCANZA clinical trial in patients with CD30-expressing mycosis fungoides and primary cutaneous anaplastic large cell lymphoma, the most common subtypes of cutaneous T-cell lymphoma (CTCL). Based on the positive results from the ALCANZA trial, a supplemental BLA for brentuximab vedotin in CTCL was accepted for filing by the FDA. The FDA granted Priority Review for the application and the Prescription Drug User Fee Act (PDUFA) target action date is December 16, 2017. brentuximab vedotin previously received FDA Breakthrough Therapy Designation in this setting;
  • Updated results from a phase I/II study of brentuximab vedotin in combination with the ahuman programmed death receptor-1 (PD-1) blocking antibody nivolumab (Opdivo®; Bristol-Myers Squibb Company) among patients with relapsed or refractory Hodgkin lymphoma;
  • Final five-year survival and durability results in patients with CD30-expressing peripheral T-cell lymphomas who received brentuximab vedotin with cyclophosphamide, hydroxydaunorubicin, and prednisone (CHP) as frontline therapy

“At this year’s ASH Annual Meeting, we will present data from 18 abstracts, highlighting several [brentuximab vedotin] clinical program advancements that support our plans to establish ADCETRIS as the foundation of care for CD30-expressing lymphomas,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“Importantly, the results of the phase III ECHELON-1 clinical trial evaluating brentuximab vedotin combination therapy in frontline advanced Hodgkin lymphoma patients was selected from over 6,000 abstracts submitted to be featured in the Plenary Scientific Session. These data are the basis for our planned supplemental biologics license application to the FDA requesting approval of brentuximab vedotin in this setting. The breadth of data being presented with brentuximab vedotin in CD30-expressing lymphomas demonstrates the power of antibody-drug conjugates with a goal of improving patient outcomes,” Siegall added

Brentuximab vedotin is currently not approved for the treatment of frontline Hodgkin lymphoma, CTCL, or as combination therapy for Hodgkin lymphoma or non-Hodgkin lymphoma.

For an overview of oral and poster presentations about antibody-drug conjugates, click here.


Ado-trastuzumab emtansine is currently the only antibody-drug conjugate available for the treatment of solid tumors.

In 2000 gemtuzumab ozogamicin, a calicheadmicin conjugates, became the first aDC to be approved in the United States. However, the drug, indicated for the treatment of CD33-positive acute myeloid leukemia (AML) was withdrawn from the market in 2010 due to treatment-related toxicity concerns.

Last Editorial Review: November 11, 2017

Featured Image: American Society of Hematology meeting 2016. Courtesy: © ASH. Used with permission.

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U.S. FDA Approves Inotuzumab Ozogamicin for Treatment of Patients with R/R B-cell precursor Acute Lymphoblastic Leukemia

The United States Food and Drug Administration (FDA) approved inotuzumab ozogamicin (Besponsa™, Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

Acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia with a poor prognosis in adults.[1] The current foundational treatment is intensive, long-term chemotherapy.[2] In 2017, it is estimated that 5,970 cases of ALL will be diagnosed in the United States, with about 2 in 5 cases occurring in adults.[3] Approximately 20 to 40% of newly diagnosed adults with ALL are cured with current treatment regimens.[4] For patients with relapsed or refractory adult ALL, the five-year overall survival rate is less than 10%.[5]

The approval was based on data from INO-VATE ALL (NCT01564784INotuzumab Ozogamicin trial to in VestigAte Tolerability and Efficacy), a randomized (1:1), open label, international, multicenter study in 326 patients with Philadelphia chromosome-negative or Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL. Patients were required to have ≥5% bone marrow blasts and to have received one or two previous induction chemotherapy regimens for ALL.

NCT01564784 (CLINICAL TRIAL / INOTUZUMAB OZOGAMYCIN / CMC-544)
Illustration: Inotuzumab ozogamicin is an antibody – drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen expressed on approximately 90 percent of B – cell malignancies , linked to a cytotoxic agent. When inotuzumab ozogamicin binds to the CD22 antigen on malignant B – cells, it is absorbed into the cell, at which point the cytotoxic agent calicheamicin is released to destroy the cell. Calicheamicin is a natural product of bacteria that was first discovered in caliche clay and was found to be toxic to normal and cancerous cells.

In this trial, patients with Philadelphia chromosome positive B cell precursor ALL were required to have disease that failed treatment with at least one tyrosine kinase inhibitor and standard chemotherapy.

Patients were randomized to receive either inotuzumab ozogamicin (n=164) or investigator’s choice of chemotherapy (n=162). Of the initial 218 randomized patients, 35.8% of those who received inotuzumab ozogamicin experienced complete remission (CR) for a median 8.0 months and 89.7% of those patients achieved minimal residual disease (MRD)-negativity. Of the patients who received chemotherapy, 17.4% experienced CR for a median 4.9 months and 31.6% of those patients achieved minimal residual disease MRD-negativity.

Adverse events
The most common adverse reactions occurring in greater than 20% of patients were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.

The most common (≥2%) adverse reactions reported as the reason for permanent discontinuation were infection, thrombocytopenia, hyperbilirubinemia, transaminases increased, and hemorrhage.

For the first cycle, the recommended dose of inotuzumab ozogamicin for all patients is 1.8 mg/m2 per cycle, administered as three divided doses on day 1 (0.8 mg/m2), day 8 (0.5 mg/m2), and day 15 (0.5 mg/m2).

The recommended dosing for subsequent cycles depends on response to treatment. Details are available in the full prescribing information. [6]

Breakthrough Therapy
A Biologics License Application (BLA) for inotuzumab ozogamicin was accepted for filing and granted Priority Review by the U.S. Food and Drug Administration (FDA) in February 2017.

In October 2015 inotuzumab ozogamicin received Breakthrough Therapy designation from the FDA in for ALL. Priority Review status accelerates FDA review time from 10 months to a goal of six months from the day of acceptance of filing, and is given to drugs that may offer major advances in treatment or may provide a treatment for which no adequate therapy exists. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in August 2017.

Antibody-drug conjugate
Inotuzumab ozogamicin is an antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen expressed on cancer cells in almost all B-ALL patients, linked to a cytotoxic agent.[7] When BESPONSA binds to the CD22 antigen on B-cells, it is internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell.[8]

The drug originates from a collaboration between Pfizer and Celltech (now UCB). Under the terms of this agreement, Pfizer has sole responsibility for all manufacturing and clinical development activities of the agent. Pfizer also collaborated with SFJ Pharmaceuticals Group on the registrational program (INO-VATE ALL) for inotuzumab ozogamicin.


Last Editorial Review: August 17, 2017

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Antibody-drug Conjugates: Technologies and Global Markets

Less than 3 decades old, antibody-drug conjugate or ADC-technology is a relatively new.  Due to many technological advances, recognition of appropriate target antigens, success in the development on novel monoclonal antibodies (mAbs) and increasing demand for biologics and biotherapeutics the market of targeted therapies, including ADCs, is rapidly increasing.

This week, ReportLinker, an award-winning market research organization published the latest industry data covering ADCs. According to the authors of the report, developed by BCC research, the global market for antibody drug conjugates was valued at $1.3 billion in 2016 and is expected to reach $4.2 billion by 2021, growing at a compound annual growth rate or CAGR of 25.5% from 2016 to 2021. [1]

In 2016, the market for ADCs in North American was valued at $588.6 million and should reach $2.0 billion by 2021, growing at a CAGR of 27.2% from 2016 to 2021. In Europe this market was valued $395.0 million in 2016 and is expected to reach $1.2 billion by 2021, growing at a CAGR of 24.1% from 2016 to 2021.

Currently approved ADCs
Advances in targeting antibodies, potent payloads and drug-linker technologies that facilitate improved ADC stability, potency and targeting efficiency have led to the development of two commercially viable ADCs. BCC Research’s goal in conducting this study is to provide an overview of the current and future characteristics of the global market for antibody drug conjugates.

The new report explores present and future strategies within the antibody-drug conjugates market, which includes, by type of payload (cytotoxic agent), by type of monoclonal antibodies and by type of linker. The inception of the market, and its demands and restraints are discussed in this report. Classification, comparisons and usage of ADC products are also presented in this report.

The authors analyzed the structure of the antibody-drug conjugate industry and broke down revenues by region, with sales estimated for the five-year period from 2016 through 2021. Applications of antibody drug conjugates and significant patents and their allotments in each category discussed.

Study background
Advancements in research have changed the way many diseases are treated. ADCs represent an innovative class of drugs that are mainly developed by conjugating already-developed or marketed small molecules and biologics. ADCs have shown great potential in cancer therapy. ADC products are becoming an important part of the biomedical industry and have the potential to replace conventional treatment options.

Research & Development spending, along with increasing competition, patent expires and new technologies are providing a new direction to the market. Advancements, new product launches and changing lifestyles are expected to influence the future growth of the market. This study looks at the majority of the systems affected by these factors.

Acquisition strategies and collaborations by companies are also covered in this report. This study also discusses the strength and weaknesses of each type company in light of the new technologies, growing competition and changing customer needs.

Scope
Antibody drug conjugates are mainly used to treat cancer and are safer and more effective than many other cancer therapies. This report focuses on the global market for antibody drug conjugate products and provides an updated review, including their basic design and application in various areas of the biomedical sciences.

The report covers three main areas of application, breast cancer, lymphoma and other cancers, including acute myeloid leukemia or AML. The scope of this study includes the current market for ADCs. The report also discusses regulatory aspects, current and developing technologies, market projections and market shares. An analysis of clinical trials, innovations and opportunities and the latest trends in ADC market are also discussed in the report.

Also included in the report is an analysis of relevant patents and profiles of companies, including Seattle Genetics, Takeda Pharmaceuticals and Genentech/Roche that lead the antibody-drug conjugate product market.

Sales data for the global and regional markets were corroborated for the present and forecasted values via statistical analysis, and sales are broken down geographically into North America, Europe, Asia- Pacific and the emerging markets. The application of ADCs in various types of cancer is discussed from both a commercial perspective and that of a research and development (R&D) perspective.

The report only covers antibody-drug conjugates in which an antibody is conjugated with small-molecule cytotoxins (payload) through a linker. Other forms of antibody conjugates such as radioisotopes conjugated with an antibody are beyond the scope of this report.

Information Sources
For this report, the authors surveyed many companies to obtain data for this study. This included manufacturers and end users of antibody-drug conjugate products. Data was also gathered from various industry sources.  The authors spoke with officials within the industry, consulted newsletters, company literature, product literature and a host of technical articles, journals, indexes and abstracts. Exhaustive database searches were conducted using key terminology. In addition, data were compiled from current financial, trade and government sources.

Methodology
Both primary and secondary research methodologies were used in preparing this study. The authors also conducted a comprehensive literature search, which included technical newsletters and journals, including ADC Review | Journal of Antibody-drug Conjugates, and many other sources and conducted interviews experts and key opinion leaders. Projections were based on estimates such as the current number of end users, potential end users, mergers and acquisitions, and market trends.

Highlights
Antibody-drug conjugates, representing the convergence of chemistry with biology, include an antibody linked with a cytotoxic drug called payload. They combine the extraordinary affinity and specificity of antibodies with the anticancer potential of payloads. Continuous efforts to improve the therapeutic potential of biologics and to develop novel efficacious drugs either by modification or derivatization led to the development of ADCs.

Over the last decades, ADCs have revolutionized the field of cancer treatment. Unlike conventional chemotherapeutics, which damage normal cells along with the cancer cells, ADCs target only cancer cells. Through the synergistic combination of monoclonal antibody with the cytotoxic drug, via a stable linker, an extremely efficacious class of anticancer drugs has been emerged. To date, three ADCs have gained entry into the market, of which only two remain. Gemtuzumab ozogamicin (Mylotarg®), marketed by Pfizer, became the first FDA approved ADC in 2000.

This drug was approved for the treatment of relapsed acute myeloid leukemia. In 2010, a decade after its approval, gemtuzumab ozogamicin was withdrawn from the market due to serious hepatotoxicity issues.

However, in late January 2017 Pfizer’s Biologics License Application (BLA) for gemtuzumab ozogamicin (Mylotarg®; previously known as CMA-676) was accepted for filing by the U.S. Food and Drug Administration (FDA). And a Marketing Authorization Application (MAA) for review by the European Medicines Agency (EMA) was validated in December 2016.[2]

The Biological License Application (BLA) was based on additional data from a Phase III study that evaluated the potential benefits of adding gemtuzumab ozogamicin to standard induction chemotherapy in the treatment of patients with acute myeloid leukemia aged 50–70 years old. The FDA’s decision on the application is expected sometime in September 2017.

Only brentuximab vedotin (Adcetris®; marketed by Seattle Genetics and Takeda Pharmaceutical) and ado-trastuzumab emtansine (Kadcyla®; marketed by Genentech/Roche), are commercially available. Brentuximab vedotin was approved in 2011 for relapsed Hodgkin lymphoma and relapsed anaplastic large-cell lymphoma, and ado-trastuzumab emtansine was approved in 2013 for human epidermal growth factor receptor 2 (HER2)-expressing breast cancer.

Technological advancements, the growing number of cancer patients and increasing demand for biologics for the treatment of chronic diseases are the prime factors that are driving the market for ADCs.

North America continues to lead the market for ADCs as it has the advanced technologies needed to develop ADCs. In addition, rising healthcare expenditures and huge government initiatives are also driving the North American market. Improving economic conditions, demand for better healthcare facilities, increasing health awareness, increasing incidence of chronic diseases and growing R&D activities will help the market for ADCs grow in Asia-Pacific.

The ADC industry involves a specialization business model, more specifically a technology licensing model. In specialization models, certain companies discover and license its ADC technology to pharmaceutical companies. The two main ADC technology companies in terms of sheer numbers of licensing deals to date are ImmunoGen and Seattle Genetics. ImmunoGen, with its maytansinoid-based targeted antibody payload (TAP-) technology, produced ado-trastuzumab emtansine with Genentech.

Brentuximab vedotin is developed by Seattle Genetics and includes the company’s ADC linker and cytotoxin expertise coupled with an antibody from Millennium Pharmaceuticals, now part of the Takeda Pharmaceutical.

Innovation in ADCs typically occur through the development of new cytotoxic agents as well as new linkers that are adequately stable and at the same time can be cleaved efficiently to deliver the cytotoxic drug. Thus, key future trends in the market for ADCs include the development of novel payloads, new linker chemistry and the site-specific conjugation technology. All these advancements are expected to lead to the development of more specialized, personalized and targeted ADCs.

The manufacturing of antibody-drug conjugates requires specific manufacturing facilities. In turn, this requires high capital investment and extensive specialized training of operators and both of these requirements indicates the trend towards the contract development and manufacturing of ADCs.

Product pipeline
The product pipeline is a key determinant of any industry’s future growth. And that is also the case with antibody-drug conjugates. The industry’s acceptance of ADC technology is evident from the continual increase in novel ADCs entering clinical trials during the past few years. During 2003-2007, 10 ADCs reached Phase I trials and this number increased to 30 during 2008-2012. About 24 novel ADCs entered Phase I trials during 2012- 2016.

A number of ADCs with promising preliminary data are in the clinical trial pipeline. Mirvetuximab soravtansine, also known as IMGN853, sacituzumab govitecan and vadastuximab talirine are in late stage phase III clinical development. These three ADCs are expected to reach the market during forecast period.

Inotuzumab ozogamicin, an anti-CD22 ADC being developed by Pfizer for the treatment of relapsed or refractory acute lymphoblastic leukemia, is expected to be approved by FDA at the end of 2017. It received priority review designation from the FDA in February 2017. Through the FDA’s priority review program, Pfizer is expected to receive the FDA’s decision on inotuzumab ozogamicin with breakthrough therapy designation within six months.

In October 2016 rovalpituzumab tesirine, also known as Rova-T, an antibody-drug conjugate being developed by AbbVie/Stemcentrx, was recognized at the 7th Annual World Antibody Drug Conjugate (ADC) Awards as the “Most Promising Clinical Candidate” for fighting cancer. The novel biomarker-specific ‘smart-bomb’ antibody-drug conjugate targets the delta-like protein 3 or DLL3 protein, expressed in more than 80% of small-cell lung cancers (SCLC) patient tumors, appears to be safe and shows efficacy in treating patients with advanced SCLC. The authors expect this investigational agent to also reach the market during the forecast period.

Market expectation
The market for ADCs was worth approximately $1.3 billion in 2016 with just two approved drugs, and its potential remains very large. Total revenues, representing product sales (collaboration and royalty revenues are not considered), are expected to be $4.2 billion worldwide by 2021 at a CAGR of 25.5% from 2016 through 2021.

These revenues reflect the estimated addition of other ADCs that are directed toward acute lymphocytic leukemia and ovarian cancer. Much of the market growth is expected to come from added indications for both the marketed ADCs. In addition, the expected approval of several other antibody-drug conjugates, such as Pfizer’s gemtuzumab ozogamicin and inotuzumab ozogamicin, during the forecast period will help the market for ADCs to grow significantly.

North America led the antibody drug conjugate market due to the presence of major pharmaceutical companies working on the development of antibody drug conjugate drugs there. Both the North American and European markets benefited from the fast track approval of ADCs. Expanded access to ADCs in Asia-Pacific and the emerging markets drove the market for ADCs in these geographies.

The two most common therapeutic areas for ADCs from 2014 to 2016 were lymphoma and breast cancer, with breast cancer representing 61.3% of ADC revenues in 2016. By 2021, with the approval of two novel ADCs to treat acute myeloid leukemia and ovarian cancer, breast cancer ADCs will represent a market share of 47.1%.


Last editorial review: July 20, 2017

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Inotuzumab ozogamicin Approved in the EU for Adult Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia

The European Commission has approved inotuzumab ozogamicin (Besponsa®; Pfizer) as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL).

This indication includes treatment of adults with Philadelphia chromosome positive (Ph+) as well as Philadelphia chromosome negative (Ph-) relapsed or refractory B-cell precursor ALL. Adults with Ph+ relapsed or refractory CD22-positive B-cell precursor ALL should have failed treatment with at least one tyrosine kinase inhibitor (TKI). With this approval, inotuzumab ozogamicin becomes the first and only antibody-drug conjugate or ADC available for patients with this type of leukemia in the European Union.

“The European Commission’s approval of inotuzumab ozogamicin represents an important milestone for patients, the oncology community and Pfizer,” said Andreas Penk, M.D., regional president, Pfizer Oncology. “This is the first approval for inotuzumab ozogamicin and provides patients in the EU, who are battling an especially hard-to-treat leukemia, with a new treatment option beyond chemotherapy.”

ALL is an aggressive type of leukemia that can be fatal within a matter of months if left untreated.[1] The goal of treatment in relapsed or refractory (resistant) ALL is to achieve complete remission without excessive toxicity so patients may proceed to additional therapeutic intervention, particularly stem cell transplant, which is the most recognized option to prolong patient survival, maintenance therapy or other therapy.[2]

In adult patients with relapsed or refractory ALL, median overall survival is just three to six months.[3][4][5] The current standard of care is intensive chemotherapy [6], which is effective in less than 50 percent of relapsed or refractory patients and associated with poor long-term survival, high toxicities, lengthy inpatient stays and continuous infusions.[7]

“Acute lymphoblastic leukemia that has recurred or is refractory following first-line therapy is a rare and rapidly progressive disease with poor prognosis,” said Professor David Marks, Department of Hematology, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom.

“The approval of inotuzumab ozogamicin provides a much needed treatment option for physicians and patients alike, that may help improve outcomes for some of the most vulnerable leukemia patients in Europe,” Marks added.

Illustration: Inotuzumab ozogamicin is an antibody – drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen expressed on approximately 90 percent of B – cell malignancies , linked to a cytotoxic agent. When inotuzumab ozogamicin binds to the CD22 antigen on malignant B – cells, it is absorbed into the cell, at which point the cytotoxic agent calicheamicin is released to destroy the cell. Calicheamicin is a natural product of bacteria that was first discovered in caliche clay and was found to be toxic to normal and cancerous cells.

INO-VATE ALL
The European Commission’s approval of inotuzumab ozogamicin is supported by results from the Phase III INO-VATE ALL trial, (NCT01564784; INotuzumab Ozogamicin trial to in VestigAte Tolerability and Efficacy) in which 326 adult patients with relapsed or refractory B-cell precursor ALL were enrolled and which compared inotuzumab ozogamicin to standard of care chemotherapy.

The INO-VATE ALL study had two primary endpoints, complete response with or without hematologic recovery (CR/CRi) and overall survival (OS).

Results from the trial were published in The New England Journal of Medicine in June 2016.

Breakthrough Therapy
In the United States, inotuzumab ozogamicin received Breakthrough Therapy designation from the Food and Drug Administration (FDA) in October 2015 for ALL. A Biologics License Application (BLA) for inotuzumab ozogamicin for the treatment of adult patients with relapsed or refractory B-cell precursor ALL was accepted for filing and granted Priority Review by the FDA in February 2017. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is August 2017.

With a growing hematology pipeline, Pfizer is committed to extending therapeutic progress in acute and chronic leukemias that leverage select pathways and mechanism of actions (MOAs). Specifically, our investigational products aim to treat some of the hardest to treat leukemias and lymphomas including, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and mantle cell lymphoma (MCL).

Antibody-drug Conjugate
Inotuzumab ozogamicin is an antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen expressed on cancer cells in almost all B-ALL patients, linked to a cytotoxic agent.[8] When the agent binds to the CD22 antigen on B-cells, it is internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell.[9]

The drug originates from a collaboration between Pfizer and Celltech (now UCB). Under the terms of this agreement, Pfizer has sole responsibility for all manufacturing and clinical development activities of the agent. Pfizer also collaborated with SFJ Pharmaceuticals Group on the registrational program (INO-VATE ALL) for inotuzumab ozogamicin.


Last Editorial Review: June 30, 2017

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Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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What to Expect at PEGS Boston 2017: A new Pathway of Progress

From the Charlestown Navy Yard to the Paul Revere House, the Old State House on Washington Street, the New England Aquarium at Central Wharf and the Faneuil Hall Market Place, Boston, MA, offers any visitor a great time. Coupled with great food (check out the Barking Crab at 88 Sleeper Street) and pubs including Cheers, McCormick & Schmick’s, Ned Devine’s Irish Pub, and Anthem Kitchen + Bar, this city is definitely a great place to visit.

May kicks off with a busy first week. The During the 7th Annual PEGSBoston conference, being held May 1 – 5, 2017 in the Seaport Worldtrade Center in Boston, MA, and organized by Cambridge Healthtech Institute, will start with a review of lessons learned from brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda) and ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche), the two marketed antibody-drug conjugates or ADCs and many novel ADCs in clinical trials.

Photo 1.0: Located in Boston, the Barking Crab at 88 Sleeper Street has become one of the city’s best-loved meeting and eating spots.

These lessons learned from these two agents as well as many ongoing ADC trials have not only enabled scientists to better understand the mechanisms of action of antibody-drug conjugates, but have also helped invigorate a new field of ADC study aimed at overcoming the challenges of poor internalization, tumor non-specificity, off-target toxicity, lack of efficacy, low expression levels and multi-drug resistance.

Scientists continue to developed novel innovative techniques – with the potential of breakthroughs leading to the next generation ADCs with improved target selection, new cytotoxic drugs as payloads, engineered antibodies or alternative effector moieties to increase half-lives and improve target specificity, optimized linker-payload chemistry to produce stable and homogeneous ADCs, and news ways in overcoming the challenges of multi-drug resistance.

Wednesday, May 3rd, will see  a full day of presentations themed ‘The Antibody-Drug Conjugates I: New Targets, Payloads and Alternative Formats.’ Scientist’s will present their creativity in the design and optimization of next-generation bioconjugates.

Bicycle-drug conjugates
Peter Park, Ph.D., Vice President, Oncology Research, Bicycle Therapeutics, will kick of  by discussing ‘bicycle-drug conjugates’ or BDC targeting MT1-MMP for treatment of solid tumors. Parl will share the latest information about the Bicycle® platform which allows a very diverse library of constrained, bicyclic peptides, generated with a chemical scaffold, to be displayed on the surface of viable bacteriophage.

Because of their relatively small size (1.5-2 kDa) they delivers advantages in tumor penetration and extravasation.  In addition, their peptidic nature offers a “tuneable” pharmacokinetic half-life and a renal route of clearance. As s result, liver and gastrointestinal tract toxicity, often seen with other drug modalities, is avoided. During his presentation, Park will share more details about the Bicycle platform and describe the discovery and development of BT1718, a potent Bicycle-drug conjugate targeting Membrane Type 1 Matrix Metalloproteinase (MT1-MTP), which is highly expressed in many solid tumors, including triple negative breast cancer and non-small cell lung cancer.  The novel drug candidate has completed GLP toxicology studies and is expected to enter the clinic in 2017 in collaboration with Cancer Research UK’s Centre for Drug Development (CDD) which will sponsor and fund a Phase Ia and Phase Ib clinical trials.

Abdurin-drug conjugates
Following Parks’ presentation, Kurt Gehlsen, Ph.D., Vice President and CSO, Therapeutics, Research Corporation Technologies (RCT) will discuss abdurin-drug conjugates which represent a new generation of targeted therapeutics.  RCT is developing this new biologics platform which is based on engineered CH2 domains (CH2D), small (12.5 kDa), immunoglobulin-derived, proteins amenable to loop and beta sheet modifications that enable binding to a target of interest. These durable protein scaffolds are called abdurins.  [1]

Existing small antibody-like scaffolds (less than 50kDa in size) have the disadvantage of a short circulating half-life caused by rapid renal clearance.  To address the short half-life disadvantage of small antibody-like scaffolds, researchers at RCT have developed abdurins which retains a long circulating half-life.

Abdurins are produced in Pichia or E. coli. They are amenable to high-throughput screening to isolate binders to targets of interest to generate multifunctional molecules or carry toxic payloads.  Abdurin immunotoxins have demonstrated improved tumor penetration compared to a monoclonal antibodies and have been conjugated to Monomethyl Auristatin E or MMAE and a deimmunized form of the ribotoxin (SarcinDI).

Researchers have shown that CH2D abdurins have a longer serum half-life (8-16 hours) compared to other scaffolds of a similar molecular weight (around 30 minutes). The smaller size and longer half-life of CH2D abdurins is expected facilitate enhanced payload delivery to solid tumors compared to standard antibody-drug conjugates.

While antibody-drug conjugates have demonstrated impressive clinical results in oncology and hematology, the extremely long half-life of the antibody (7-21 days) combined with a short half-life of the linkers and cytotoxic agents (hours) limits their effectiveness and can crease unnecessary toxic side effects.

Researchers at RCT think that half-life of CH2D abdurins may be better suited to linker and drug half-life.  Their small size may help deliver more of the cytotoxic drug to a tumor than conventional ADCs. Hence, they believe that CH2D abdurins-drug conjugates 0r or abdurin immunotoxins may represent the next generation ADC therapeutics with improved efficacy and reduced toxicity.

BCMA-Targeted Amanitin-based ADCs
Another approach is represented by BCMA-Targeted Amanitin-based ADCs. Andreas Pahl, Ph.D., CSO, Heidelberg Pharma will present updated data about antigen-targeted amanitin-conjugates or ATACs.

ATACs represent a new class of antibody-drug conjugates using the payload Amanitin. This payload introduces a novel mode of action into oncology therapy, the inhibition of RNA polymerase II. The technology platform around ATACs includes amanitin supply, site-specific conjugation, demonstrated safety profile and biomarker.

A BCMA-ATAC has been selected based on favorable preclinical data to start the clinical development of the first ATAC.

Pyrrole-Based KSP Inhibitors
Hans-Georg Lerchen, Ph.D., Principal Scientist, Drug Discovery, MedChem, Bayer AG will discuss the development of potent and selective ADCs targeting different antigens with Pyrrole-Based KSP Inhibitors as novel payload class.

Over the last decade, small molecule inhibitors of kinesin spindle protein (KSP/Eg5) have generated interest due to their high anti-tumor potency. Inhibition of kinesin spindle protein (KSP) is a relatively novel mechanism for treatment of cancer.  Scientists believe that KSP has the potential to overcome limitations associated with currently employed cytotoxic anticancer chemotherapeutic agents.  Furthermore, the identification of KSP as a payload class with a novel mode of action is expected to increase therapeutic options and potentially help to overcome resistance. [2]

A new pyrrole subclass of KSP inhibitors with sub-nanomolar potency against a large panel of tumor cell lines has been established as a versatile new payload class for the generation of potent and selective ADCs against different targets.

Novel Linkers and Payloads
John Babcook, Ph.D., Senior Vice President, Discovery Research, Zymeworks is expected to discuss ways to expand the therapeutic window of antibudy-drug conjugates with Zymelink™ linkers and payloads

The Zymelink conjugation platform is includes a modular suite of proprietary payloads, linkers and site-specific conjugation technologies designed for the targeted delivery of therapeutics with optimal efficacy and safety profiles.  The technology platform offers customizable cleavable and non-cleavable linkers that is compatible with a variety of small molecule therapeutics. Zymelink is compatible with traditional monoclonal antibodies, Azymetric™ (bispecific) and AlbuCORE™ (multispecific) platforms for the development of next-generation biotherapeutics and ensures the production of homogeneous drug products while maintaining systemic stability and enabling the efficient release of its payload to target cells after internalization. The technology imparts homogeneity of the antibody-drug conjugate with fixed drug-antibody ratios ( DAR), preserve antibody Fc effector function to facilitate the recruitment and activation of immune cells and maintain antibody pharmacokinetics through FcRn engagement.

In addition to the company’s proprietary linker technology, Zymeworks is developing a series of proprietary cytotoxic payloads, spanning multiple classes, that possess highly potent anti-tumor activity against a broad range of cancer cell types. A key competitive advantage for these cytotoxins, together with the ZymeLink™ platform, is their exceptional anti-tumor efficacy and tolerability in vivo, resulting in the ADCs having a large therapeutic window.

Latest Developments of ADCs using SMARTag™ Technology
David Rabuka, Ph.D., Global Head of Research & Development, Chemical Biology, Biologics Research & Development, Catalent Pharma Solutions will present an overview of the latest developments of antibidy-drug conjugates using Catalent’s SMARTag™ technology platform/

The SMARTag technology platform enables scientists to develop precise, programmable, site-selective chemical protein modifications. Leveraging the target sequence of Formylglycine Generating Enzyme (FGE), Rabuka and his team chemoenzymatically modify proteins to generate a precisely placed aldehyde functionality that can be chemically elaborated.  During this year’s PEGS Boston, the company will present a novel protein modification platform and its application to generating ADCs, including our new conjugation chemistries and linkers.

Antibody-drug Conjugates with Novel DNA Alkylating Agents
In the afternoon (Wednesday, May 3rd) Ravi J. Chari, Ph.D., Vice President, Chemistry & Biochemistry, ImmunoGen will discuss the design and preclinical evaluation of ADCs with novel DNA alkylating agents.

With over 50 antibody-drug conjugates in clinical development, there is a growing interest in ADCs for the treatment of cancer and hematological malignancies. As part of ImmunoGen’s effort to expand the available toolbox of cytotoxic payloads, scientists have designed so called indolino-benzodiazepine dimers, also known as IGNs. Chari will discuss the chemical design and preclinical data for this new class of potent DNA-alkylating agents and representative IGN ADCs.

Novel DNA-Targeting Payloads
Puja Sapra, Ph.D., Vice President and CSO, Target Therapeutics Unit, Oncology Research & Development, Pfizer, will review the development of gemtuzumab ozogamicin (Mylotarg®) and inotuzumab ozogamicin (CMC-544). In her talk Sapra will furthe explore the next generation of DNA-damaging antibody-drug conjugates being developped by Pfizer.

HuMax-AXL-MMAE
Following the Thursday morning remarks by Vijay Chudasama, Ph.D., Lecturer, Organic Chemistry and Chemical Biology, University College London, David Satijn, Ph.D., Director, New Antibody Products, Genmab will discuss how Humax-AXL MMAE will elimination of multidrug-resistant melanoma. Satijn shows how AXL is overexpressed in many types of cancer, including melanoma, and is associated with EMT and increased invasiveness of tumors. He will further explain how AXL is also upregulated upon resistance to a variety of therapies including the oft-used BRAF and MEK inhibitors in melanoma and how HuMax-AXL-MMAE, being developped by Genmab, shows efficacy in AXL-expressing melanoma CDX and PDX models.

Satijn’s presentation is followed by a presentation by Julian Spallholz, Ph.D., Professor, Nutritional Biochemistry, Nutritional Sciences, Texas Tech University. Spallholz is expected to explain how women with Her/2 + breast cancer (BC) treated with trastuzumab (Herceptin®; Genentech/Roche) often relapse with their cancer becoming Herceptin resistant.  To overcome resistance ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche) can be used. Spallholz will explain how his team has replaced emtansine with a small redox selenium moiety (Mab-SeCN) that redox cycles and increases intracellular BC oxidative stress by generating intracellular superoxide and H2O2. The results confirm that an Se-Herceptin® antibody-drug conjugate is more cytotoxic to trastuzumab resistant and ado-trastuzumab emtansine treated trastuzumab resistant JIMT-1 BC cells.

REsidue-SPEcific Conjugation Technology
Jared Spidel, Ph.D., Principal Scientist, Antibody Core, Morphotek, will follow Spallholz presentation. He will discuss how Morphotek’s cysteine-specific conjugation method exploits a unique intrachain disulfide bond in the light chain of rabbit antibodies between cysteine residues at 80 and 171 of the variable and constant domains.

The company’s humanization strategy allows retention of the C80 with a free thiol group that is amenable for residue-specific conjugation. The company’s C-terminal lysine-specific linkage method employs the transglutaminase enzyme catalyzing formation of an isopeptide bond between the IgG C-terminal K447 and a variety of glutamine-based payloads. Antibody-drug conjugates prepared using the company’s RESPECT technology produced uniform drug-to-antibody ratios and were shown to be highly potent and specific in vitro and in vivo.

Optimizing Linker and Conjugation Chemistry
Bradley L. Pentelute, Ph.D., Professor, Chemistry, Massachusetts Institute of Technology will discuss how a robust bioconjugation method using cysteine arylation enables the development of site specific antibody-drug conjugates at cysteine residues within peptides, proteins, and antibodies. Pentelute and his team developped two approaches using either perfluoroaryl-cysteine SNAr chemistry or organometallic palladium reagents. They discovered a self-labeling four-residue sequence that enables regioselective conjugation at only one cysteine residue within an intact antibody containing natural amino acids.

Novel Lysosoma Cleavage Linker Leads to Potent and Stable Duocarmycin Conjugates
Duocarmycin is very potent DNA alkylating agent. However duocarmycin as small molecule have not been successful in clinical trials due to its toxicity. However, duocarmycin as payload for an antibody-drug conjugates has been explored by several companies.

Ying Sun, Ph.D., Associate Director of Chemistry, Ambrx, shows that while the linker design for duocarmycin has been challenging scientist at Ambrx have developed a new linker design with novel lysosomal cleavage mechanism, which leads to potent and stable duocarmycin conjugates.

Vijay Chudasama, Ph.D., Lecturer, Organic Chemistry and Chemical Biology, University College London, will conclude The Antibody-Drug Conjugates I: New Targets, Payloads and Alternative Formats sessions with a presentation on fine-tuning functional disulfide re-bridging to enable the formation of homogeneous antibody-conjugates and exploring novel ADC avenues.

Chudasama will detail the latest data on next generation maleimide and pyridazinedione reagents for the site-selective modification of antibodies (robust serum stability, in vitro selectivity, in vivo efficacy, and an update our first-in-class reagents that effect both disulfide reduction and functional re-bridging). He will also present, how his team of scientists has been able to use their platforms to create bispecifics, and a novel strategy for making DAR 2 constructs from a native antibody scaffold.

With such an exciting program, make sure to visit Boston to attend the 2017 edition of PEGSBoston.


Last Editorial Review: April 30, 2017

Featured Image: Seaport Worldtrade Center; Boston, MA. Courtesy: © 2017 Fotolia. Used with permission.

Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Study Shows High Remission Rate in Leukemia Patients Treated with Inotuzumab Ozogamicin

In an open-label, randomized Phase III INO-VATE ALL study, also known as study 1022, of the investigational drug inotuzumab ozogamicin, also known as CMC-544 (Pfizer), a statistically significant percentage of patients with acute lymphoblastic leukemia (ALL) whose disease had relapsed following standard therapies, qualified for stem cell transplants.

Acute lymphoblastic leukemia is an aggressive type of leukemia with a poor prognosis in adults.[1] The current foundational treatment is intensive, long-term chemotherapy.[2] In 2016, it is estimated that 6,590 cases of ALL will be diagnosed in the United States, with about 2 in 5 cases in adults.[3] Approximately 20 to 40 percent of newly diagnosed adults with ALL are cured with current treatment regimens.[4] For patients with relapsed or refractory adult ALL, the five-year overall survival rate is less than 10 percent.[5]

EHA-Copenhagen_2016The study evaluated the safety and efficacy of inotuzumab ozogamicin as compared with investigator-choice chemotherapy in 326 adult patients with relapsed or refractory CD22-positive ALL. Results showed improvement over chemotherapy on a number of measures including complete hematologic remission and progression-free survival (PFS). Updated results and newly available overall survival (OS) data were also presented as a late-breaking oral presentation (#LB2233) at the 21st Congress of the European Hematology Association (EHA) 2016 Annual Meeting in Copenhagen, Denmark.[6]

Inotuzumab ozogamicin is an antibody-drug conjugate linking an antibody that targets CD22, a protein found on the surface of more than 90% of ALL cells, conjugated to the cytotoxin calecheamicin. [7][8]Once the agent binds to CD22, it is thought to be internalized into the cell, where the cytotoxic agent is released to destroy the cell. [8]

Complete remission
The study, which revealed complete remission rates of nearly 81% and significantly longer progression-free and higher overall survival rates than with standard therapies, was conducted at The University of Texas MD Anderson Cancer Center. Study findings were reported in the June 12 online issue of the New England Journal of Medicine. [9]

Kantarjian_MD_Anderson
Photo 1.0: Hagop Kantarjian, MD, Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.

“Relapsed or refractory ALL is an aggressive leukemia in urgent need of new treatment options as about half of adult patients will not respond to chemotherapy or will see their disease return,” noted Hagop Kantarjian, MD, Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.

“Forty-one percent of all patients with acute lymphoblastic leukemia participating in the study were able to proceed to transplant after receiving inotuzumab ozogamicin compared with the 11% we have seen qualify through standard chemotherapy,” he said.

“Given that stem cell transplant is considered the only curative treatment option, the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging,” Kantarjian explained.

“The efficacy results seen in patients treated with inotuzumab ozogamicin in this study are impressive, particularly median progression-free survival, high rates of hematological remission and absence of minimal residual disease. These results suggest inotuzumab ozogamicin, if approved, could be a valuable new addition to currently available treatment options.”

Stem cell transplants
Donor stem cell transplants generally are considered curative for this aggressive form of leukemia with more than 6,500 American adults expected to be diagnosed with the disease in 2016. However, patients must be in complete remission before they are eligible for transplant.

Current therapies for adults with newly diagnosed B-cell ALL result in complete remission rates (CR) of 60 to 90%. However, many of those patients will relapse and only about 30 to 50% will achieve long-term, disease-free survival lasting more than three years.

“Standard chemotherapy regimens result in complete remission in 31 to 41% of patients who relapse earlier, and just 18 to 25% in those who relapse later,” said Kantarjian. “Patients in the inotuzumab ozogamicin study had remission rates of 58%, higher than previously reported, possibly due to patients being treated later in the disease course.”

Study results
The INO-VATE ALL study had two independent primary endpoints, complete response with or without hematologic remission and OS. INO-VATE ALL met its first primary endpoint of complete response, which was significantly better with inotuzumab ozogamicin compared to chemotherapy (80.7% [95% CI, 72%-88%] vs. 29.4% [95% CI, 21%-39%], P<0.001).

Inotuzumab ozogamicin also significantly extended PFS compared to chemotherapy (HR: 0.45 [97.5% CI, 0.34-0.61], P<0.001; median PFS, 5.0 vs. 1.8 months, in their respective arms). The second primary endpoint of OS showed a strong trend toward longer OS for patients treated with inotuzumab ozogamicin compared to chemotherapy, but did not reach the level of statistical significance (p < 0.0104) for the trial (HR: 0.77 [97.5% CI, 0.58-1.03], one-sided P=0.0203; median OS, 7.7 months [95% CI, 6.0-9.2] vs. 6.7 months [95% CI, 4.9-8.3]). The two-year OS rate for inotuzumab ozogamicin was 23 percent (95% CI, 16%‒30%) compared to chemotherapy at 10 percent (95% CI, 5%‒16%).

“Adult patients with relapsed or refractory ALL have a five-year survival rate of less than 10 percent, making these patients particularly difficult to treat. To see remission rates and two-year survival rates that are more than doubled compared to standard of care chemotherapy is very gratifying,” said Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development.

“We believe these data add to the growing body of evidence that supports inotuzumab ozogamicin as an important potential treatment option in adults with relapsed or refractory ALL,” Rothenberg added.

Results from INO-VATE ALL also showed patients treated with inotuzumab ozogamicin achieved high rates of minimal residual disease (MRD) negativity (78.4% [95% CI, 68%-87%; P<0.001]), and experienced a duration of response (DOR) of 4.6 months (95% CI, 3.9-5.4; HR: 0.55; P<0.034).

In comparison, 28.1 percent (95% CI, 14%-47%; P<0.001) of patients treated with chemotherapy achieved MRD negativity and median DOR was 3.1 months (95% CI, 1.4-4.9; HR: 0.55; P<0.034). More patients also proceeded to stem-cell transplant with inotuzumab ozogamicin compared to standard chemotherapy (41% vs. 11%, P<0.001).

Adverse events
Overall, the study reported moderate side effects, the most common being cytopenia, including febrile neutropenia (16% vs. 22%), a disorder that reduces blood cell production, and liver toxicity. Common nonhematologic treatment-emergent side effects included nausea (32%), headache (28%) and pyrexia (27%). Patients in the chemotherapy arm experienced nausea (47%), pyrexia (43%) and diarrhea (40%).

Additionally, any-grade veno-occlusive liver disease (VOD) occurred more frequently in patients treated with inotuzumab ozogamicin compared to chemotherapy (11% vs. 1%). Five patients taking inotuzumab ozogamicin developed VOD during treatment and 10 patients developed VOD after subsequent stem cell transplant. Among those taking chemotherapy, one patient developed VOD after transplant. No cases of VOD occurred during treatment with chemotherapy.

Breakthrough Therapy Designation
In October 2015 the US Food and Drug Administration (FDA) granted a breakthrough therapy designation for inotuzumab ozogamicin, based on the Phase III INO-VATE ALL trial data.[10]

The FDA’s breakthrough therapy designation is a regulatory process designed to expedite the development and review of novel, investigational, drugs that are intended to treat serious conditions in which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement compared to available therapy on a clinically significant endpoints.

Funding for this study was provided by Pfizer, Inc.


Last Editorial Review: June 13, 2016

Featured Image: Science laboratory test tubes. Courtesy: © Fotolia. Used with permission.

Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Clinical Updates Confirming Advances and Meaningful Benefits for Patients

Earlier this year, during the meetings of the American Association for Cancer Research (AACR), held April 16-20 in New Orleans, LA, and the Protein and Antibody Engineering Summit (PEGS) in Boston, MA (April 25 – 29), multiple presentations showed how antibody-drug conjugates (ADCs) have, over the last decade, really revolutionized the field of cancer chemotherapy.

With good reason, ADCs have, essentially, become all the rage for pharmaceutical oncology drug development pipelines.

While the success of the currently approved and marketed ADCs, brentuximab vedotin (Adcetris®; Seattle Genetics) and ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche/Immunogen), has, as one expert explained, been tough to follow, it’s exciting to see that the hard work by dedicated scientists and clinical investigators is indeed bearing fruit!

With >50 ADCs in clinical trials, and an average clinical development time of ~6 – 12 years, the expectation is that in the next 3 – 4 years the number of new, approved, ADCs will increase dramatically.

It’s indeed exciting to see that scientists have met, and are continuing to meet, a number of these and other challenges … in the development of novel antibody-drug conjugates…

Hurdles
The complexity of ADCs present unique development challenges. But what are some of the hurdles to be expected in bringing novel ADCs to the clinic? Following the first generation of ADC chemistries, what are some of the preclinical and clinical lessons and how have these experiences been applied?

New ADCs in clinical development are directed against a range of different targets. However, there are only a limited number of cytotoxic drugs, including calicheamicin, auristatins, maytansinoids, duocarmycins and pyrrolobenzodiazepines (PBDs) confirming the difficulties of finding fitting cytotoxic drugs as payloads in ADCs. How do these highly potent agents support an average of drug-to-antibody ratio (DAR) of 2 to 4? Are they not too hydrophobic? Are they linkable? Are they accessible by simple synthetic pathways? Manufacturable? Is there a relationship between targeted receptor number and the potency of the targeted cytotoxic drug required for therapeutic efficacy?

How can we design a linker in a ligand-targeted drug conjugate that is stable in circulation and cleavable upon endocytosis into tumor cells? What about a case for moderate toxic payloads? What about the sensitivity of cytotoxic agents to multidrug resistance (MDR) mechanisms?

Meeting the challenge
It’s indeed exciting to see that scientists have met, and are continuing to meet, a number of these and other challenges including how to improve the therapeutic index, the selection of the optimal target, a better understanding of mechanism of action (MOA) of existing and new ADCs, how to manage and understand off-target toxicities, as well as the selection of appropriate clinical settings where these novel, targeted, drugs may have the highest clinical benefit. [1]

During the 2016 AACR meeting in April, results from the I-SPY2 TRIAL, in which investigators tested if ado-trastuzumab emtansine + pertuzumab could bring a substantially greater proportion of patients to the primary endpoint of pathological complete response (pCR) compared with paclitaxel + trastuzumab, showed that the combination of ado-trastuzumab emtansine + pertuzumab substantially improved pCR for all subgroups of HER2-positive breast cancers compared with those in the control group. [2]

Investigators expect that this combination will most likely succeed in a confirmatory 300-patient, neoadjuvant, phase III, randomized trial testing ado-trastuzumab emtansine + pertuzumab against paclitaxel + trastuzumab. [2]

PEGS Summit
In late April, during the PEGS Summit in Boston, attendees discussed the complexity of antibody-drug conjugates with its many moving parts. The confirmed consensus is that these ‘moving parts’ make the field of antibody-drug conjugates incredibly challenging, and yet, it offers scientists a full spectrum and potential for innovation. From new targeting ligands to new conjugation methods, from multiple payloads to changing the drug-antibody ratio (DAR), all these are challenging the convention for the design and development of next-generation ADCs.

Progress in site-specific conjugation modalities, optimization of linkers with balanced stability and identification of novel, potent cytotoxic agents are expected to pave the way for a better understanding of factors such as ADC efficacy, PK and safety. A robust clinical pipeline, evolving clinical data, technological advancements and a better understanding of the biology of cancer and hematological malignancies, is expected to aid the development of these novel ADCs.

ASCO 2016
This year, the theme of the annual meeting of the American Society of Clinical Oncology (ASCO) to be held June 3 – 7 in Chicago, Ill. is Collective Wisdom: The Future of Patient-Centered Care and Research, emphasizing that the combined knowledge from various disciplines, cancer types, treatment approaches, and big data technologies is essential to progress. [3]
The 2016 theme is expected to reinforces the inextricable link – a necessity – between ongoing clinical research and advances in patient-centered care. This theme is expected to be evident when the latest, most exciting discoveries, based on a better understanding of cancer biology and chemistry – crucial in the development of novel ADCs – will be presented.

As the executive editor of ADC Review / Journal of Antibody-drug Conjugates (published by InPress Media Group), I’m looking forward to see the updated results from a large number of (ongoing) clinical trials during ASCO this year. In addition to updates for brentuximab vedotin and ado-trastuzumab emtansine, oral and poster presentations during ASCO will include the latest – often late breaking abstracts – for [3]:

  • Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate (IMMU-132), being developed by Immunomedics;
  • Rovalpituzumab tesirine (Rova-T/SC16LD6.5; Stemcentrx/AbbVie), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate for the treatment of recurrent or refractory small cell lung cancer (SCLC);
  • An anti-PSMA ADC (Ambrx) being developed for the treatment of patients with prostate cancer and glioblastoma multiforme;
  • Enfortumab vedotin (Agensys), a human anti-nectin-4 antibody conjugated to monomethyl auristatin E (MMAE) for the treatment of multiple solid tumors;
  • Inotuzumab ozogamicin (Pfizer) for the treatment of patients with relapsed/refractory acute lymphoblastic leukemia;
  • Anetumab ravtansine (BAY 94-9343) an anti-mesothelin antibody drug conjugate for the potential treatment of mesotheliomas as well as ovarian and pancreatic cancers;
  • ABBV-399 (AbbVie), an antibody drug conjugate targeting c-Met, in patients with advanced solid tumors;
  • Mirvetuximab soravtansine (IMGN853; Immunogen), a folate receptor alpha (FRα)-targeting antibody-drug conjugate in clinical trials as single agent activity in platinum-resistant epithelial ovarian cancer;
  • Lifastuzumab vedotin, also known as DNIB0600A and RG-7599 is being developed by Genentech/Roche. In clinical trials lifastuzumab vedotin is compared to pegylated liposomal doxorubicin for the treatment of patients with platinum-resistant ovarian cancer.

In addition to these ADCs, results are expected for SAR566658, ABT-414 and other ADCs.

This year, the annual meeting of the American Society of Clinical Oncology is expected to draw approximately 30,000+ scientists, clinicians, (patient) advocates, and others who will listen, learn and discuss advances in the treatment of cancer.

Our editorial team will be present in Chicago to bring you exciting news and (late) breaking (clinical) updates as well as interviews with the dedicated scientists, physicians and other professionals involved in ongoing research.

Expect to see reports and stirring news from ongoing clinical trials with novel antibody-drug conjugates, confirming the exciting advances and meaningful benefits for patients – now and in the future.


Click here to see an overview of oral and poster presentations of antibody-drug conjugates to be presented at ASCO this year. For additional information to plan your meeting attendance, visit ASCO’s iPlanner page.

Last Editorial Review: May 10, 2016

Featured Image: The Boston Seaport World Trade Center’s classic façade dates from 1913, when it was Commonwealth Pier. Every year, CHI’s flagship biologics event, the Protein and Antibody Engineering Summit (PEGS), is being held in Boston’s trendy Seaport District. Courtesy © 2016 Sunvalley Communication/Evan Wendt. Used with permission.

Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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