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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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New Hydrophilic Auristatin Payload Improves Antibody-Drug Conjugate Efficacy and Biocompatibility

Antibody-drug conjugates or ADCs, which link an antibody to a potent, small-molecule, cytotoxic, cell-killing, chemotherapeutic agent, use the target-specificity of monoclonal antibodies or antibody fragments, to adhere exclusively to specific membrane receptors that are characteristic of tumor cells. Following internalization, the potent, anti-cancer drugs, are releases and kill the malignant cell.

This approach creates an excellent control mechanism of drug activation, resulting in an increase of the therapeutic window and, thereby, increasing the use attached drug. However, the therapeutic window of antibody-drug conjugates is still quite narrow, making research in developing a more safe and efficacious ADC technology with a wider therapeutic window a viable field of study.

Current technology
Antibody-drug Conjugates are currently used for the treatment of lymphoma and metastatic breast cancer. Today, four Antibody-drug Conjugates have been approved by the U.S. Food and Drug Administration (FDA). These agents include brentuximab vedotin (Adcetris®; Seattle Genetics) for Hodgkin and anaplastic large cell lymphoma, ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche) for HER2-positive metastatic breast cancer, gemtuzumab ozogamicin (Mylotarg®; Pfizer) for acute myeloid leukemia and inotuzumab ozogamicin (Besponsa®; Pfizer) for the treatment of acute lymphoblastic leukemia.

Unique properties
The unique properties of an antibody-drug conjugate are determined by the balance of its components. One key part is the cytotoxic payload. The efficacy of of the payload are determined by the drug-to-antibody ratio (DAR) – the number of attached drug molecules to the antibody.

Homogeneous DAR = 8 antibody-drug conjugate can be easily prepared by conjugation to the four accessible antibody hinge cystines. And antibody-drug conjugates with higher drug-to-antibody ratios have greater in vitro potency than the current clinically approved ADCs with a DAR of 2 – 4. Furthermore,  the higher DAR antibody-drug conjugates are especially effective against cells with low copy numbers of the target antigen. [1]

However, many clinical programs with higher a DAR have suffered from unwanted toxicity and insufficient efficacy against tumors. In turn, the use of hydrophobic payloads has effectively permitted only DAR = 2–4. This is, in part, due to poor pharmacokinetics and aggregation and systemic exposure. For example, DAR = 8 monomethyl auristatin E (MMAE) antibody-drug conjugates have been shown to be inferior to both ADCs with a drug loading of DAR of 2 and DAR of 4 in vivo. [1][2]

Researchers have shown that by reducing hydrophobicity of homogeneous antibody-drug conjugates it is possible to improve the pharmacokinetics and therapeutic index. These researchers demonstrated that by masking the hydrophobic payloads by hydrophilic linker moieties,antibody-drug conjugates with a drug loading of DAR = 8 and improved in vivo biodistribution and efficacy can be achieved [3].

A novel payload
Tero Satomaa and colleagues at  Glykos Finland, in Helsinki, Finland and OcellO, in Leiden, The Netherlands, generated a novel homogeneous antibody-drug conjugate (MC-Val-Cit-PABC-MMAU) with a DAR = 8.  Their antibody-drug conjugate includes a novel monomethyl auristatin β-D-glucuronide (MMAU).[4]

Their glycoside payload contributed to overall hydrophilicity of the antibody-drug conjugates, reducing aggregation. Furthermore, compared to standard drug loading of DAR 2 and 4, the cytotoxicity of the homogeneous ADC with a DAR of 8 was improved to low-picomolar IC50 values against cancer cells in vitro.

Although unconjugated MMAU was relatively non-toxic to cells, the bystander efficacy was restored after internalization and subsequent cleavage of the glycoside. The researchers concluded that their novel monomethyl auristatin β-D-glucuronide (MMAU) antibody-drug conjugate with a DAR of 8 was effective against target antigen-expressing xenograft tumors. Furthermore, studied in 3D in vitro patient-derived xenograft (PDX) assays, these antibody-drug conjugates outperformed clinically used ADC.

Overall, the researchers found that MMAU is a promising novel payload and can overcome many challenges of ADC technology. They demonstrated that the increased hydrophilicity of the payload contributed to the hydrophilicity and stability of antibody-drug conjugates as well as the safety to non-target cells, while significantly improving cytotoxicity to malignant cells and enabling bystander efficacy.


Last Editorial Review: June 22, 2018

Featured Image: Scientist using microscope in the laboratory. Courtesy: © 2010 – 2018. Fotolia Used with permission.

Copyright © 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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New Phase I Study with SGN-CD48A in Relapsed or Refractory Multiple Myeloma

Multiple myeloma is an incurable hematologic malignancy formed by malignant or transformed plasma cells in which the cancerous plasma cells can crowd out healthy blood cells, impair bone strength and weaken the immune system.

And while this disease is a relatively uncommon cancer (in the United States, the lifetime risk of getting multiple myeloma is 1 in 143 or 0.7%), the American Cancer Society estimates that about 30,770 people will be diagnosed (16,400 in men and 14,370 in women) with multiple myeloma and about 12,770 patients will die (6,830 in men and 5,940 in women) as a results of the disease in the United States for 2018.

“[Although relatively uncommon,] multiple myeloma is the second most common blood cancer in the United States and remains an incurable disease despite recent medical advances,” noted Robert Lechleider, M.D., Senior Vice President, Clinical Development at Seattle Genetics.

Today, multiple myeloma is managed with sequential lines of treatment that typically yield shorter durations of disease control with each subsequent relapse, and some patients receive more than four lines of treatment over the course of their disease.

As a results, there exists a major unmet medical need for patients with multiple myeloma.

“[To effectively treat multiple myeloma and to increase the stringency and durability of remissions] patients are in need of new targeted treatment options,” Lechleider added.

Antibody-drug Conjugate
SGN-CD48A, a potent CD48-targeting antibody-drug conjugate or ADC, utilizing the potent microtubule disrupting cytotoxic agent monomethyl auristatin E (MMAE) and a PEGylated β-glucuronidase-cleavable linker system that can enable a higher drug-to-antibody ratio or DAR, is one of the potential therapies for the treatment of multiple myeloma.

The investigational drug includes a humanized anti-CD48 monoclonal antibody to which eight molecules of MMAE have been conjugated.

The proprietary linker technology developed by Seattle Genetics incorporates a PEG side chain and self-stabilizing maleimide designed to achieve homogenous DAR with decreased plasma clearance and increased preclinical antitumor activity. As a result, the investigational ADC has demonstrated to be highly stable in circulation and release an increased amount of MMAE upon internalization into CD48-expressing cells, producing greater antitumor activity in preclinical studies.

CD48
CD48, also known as SLAMF2 (Signaling Lymphocyte Activation Molecule family member 2), is a GPI-anchored membrane protein in the SLAM family of immunoreceptors expressed in 90% (90/100) of human multiple myeloma patient samples examined by flow cytometry.

It is also expressed on B and T lymphocytes, natural killer (NK) cells, and other immune cell types where it functions to modulate immune cell activation, proliferation, and differentiation.

Mode of action
Following binding of CD48 at the myeloma cell surface, SGN-CD48A internalizes and traffics to lysosomal vesicles. This is followed by intracellular MMAE drug released from SGN-CD48A in myeloma cells induced cell cycle arrest at G2/M phase, phospho-histone H3 (Ser-10) phosphorylation, and caspase 3/7 dependent apoptotic cell death.

In preclinical development SGN-CD48A has demonstrated potent cytotoxic activity (EC50 values 1.0 – 11 ng/mL) against a panel of human multiple myeloma cell lines, with CD48 expression levels of 135,000 – 480,000 receptors per cell. However, the drug had negligible cytotoxic activity against normal resting human B, NK, and T lymphocytes.

Phase I trial
As part of the development SGN-CD48A, a first patient was dosed in a phase I clinical trial evaluating the safety and tolerability of the investigational agent.

“SGN-CD48A uses our latest ADC technology, and the initiation of this phase I trial in relapsed or refractory multiple myeloma highlights our continued leadership in ADCs as we address this challenging disease,” Seattle Genetics’ Lechleider added.

The phase I study is a multicenter open-label dose-escalation trial designed to enroll approximately 75 patients with relapsed or refractory multiple myeloma.

Schedule
In this phase I clinical trial SGN-CD48A will be administered at an initial dosing interval of every three weeks. The primary objectives of the trial are to evaluate the safety and tolerability of SGN-CD48A and to identify the maximum tolerated dose (MTD). Key secondary objectives include assessing the antitumor activity and identifying the recommended single-agent dose and schedule.


Last Editorial Review: March 14, 2018

Featured Image: Scientist researching in the laboratory. Courtesy: © 2018 Fotolia. Used with permission.

Copyright © 2013 – 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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Updated Phase I Data for Ladiratuzumab Vedotin in Patients with Triple Negative Breast Cancer

Data from an ongoing phase I clinical trial evaluating ladiratuzumab vedotin, also known as SGN-LIV1A, in patients with metastatic triple negative breast cancer presented at the 2017 San Antonio Breast Cancer Symposium (SABCS), taking place December 5-9, 2017 in San Antonio, Texas, show 29% Objective Response Rate (ORR) at the recommended monotherapy dose in patients with heavily pretreated disease.

Enrollment for the trial is ongoing. [1]

Breast cancer is the most common cancer among women in the United States, excluding some forms of skin cancer. Of the more than 250,000 new cases expected in the United States this year, about 15% to 20% will be diagnosed a tripple negative breast cancer or TNBC, which has a particularly poor prognosis.

Breast cancers are commonly categorized by the expression (or lack thereof) of three proteins, which include the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). However, TNBC lacks expression of these three breast cancer-associated proteins that serve as key therapeutic targets. About one-third of breast cancer patients will eventually develop recurrent or metastatic disease, and current therapies for metastatic TNBC only delay progression. New treatment approaches are needed to improve outcomes for women with TNBC, where there are currently no available targeted therapies.

Investigational agent
Ladiratuzumab vedotin, being developed by Seattle Genetics, is an investigational antibody-drug conjugate or ADC designed to deliver a potent and clinically validated microtubule-disrupting agent (read: cell killing drug), monomethyl auristatin E or MMAE, to cancer cells which express the protein LIV-1.  This protein is a transmembrane protein and downstream target of STAT3 and is expressed on multiple solid tumors including breast, prostate, melanoma, ovarian, uterine, and cervical cancers. In breast cancer, LIV-1 is associated with lymph node involvement and metastatic progression. [1]

Linked via a protease-cleavable linker, using the same technology as brentuximab vedotin (Adcetris®; Seattle Genetics), ladiratuzumab vedotin bind to LIV-1 on cancer cells and release the cell-killing agent into target cells upon internalization. The investigational agent may also cause antitumor activity through other mechanisms, including activation of an immune response.

Phase I results
“Overall, the phase I results we’ve presented at the annual SABCS confirm previous findings that single-agent treatment with ladiratuzumab vedotin was generally well-tolerated and showed encouraging antitumor activity in patients with heavily-pretreated metastatic TNBC,” said Robert Lechleider, M.D., Senior Vice President, Clinical Development at Seattle Genetics.

“We continue to evaluate ladiratuzumab vedotin monotherapy in TNBC, with planned combination studies in earlier lines of treatment, demonstrating our overarching commitment to improve the health of women with this devastating disease,” Lechleider added.

Findings from this ongoing phase I study of ladiratuzumab vedotin in patients with metastatic breast cancer were last presented at the 2016 SABCS. The updated results presented this year in a spotlight session describe the safety, tolerability, and antitumor activity of ladiratuzumab vedotin in 28 additional patients with TNBC.

Trial design
A total of 81 patients with LIV-1-expressing metastatic breast cancer were treated with ladiratuzumab vedotin monotherapy given every three weeks. Patients enrolled in the study had received a median of four prior systemic metastatic therapies.

Of these patients, 63 were diagnosed with TNBC and 18 had hormone receptor-positive / human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer.

At the completion of dose escalation at doses ranging from 0.5 to 2.8 milligrams per kilogram (mg/kg), TNBC expansion cohorts were opened at 2.0 and 2.5 mg/kg to further evaluate safety and antitumor activity of ladiratuzumab vedotin in metastatic TNBC patients. Based on efficacy and safety, the recommended dose is 2.5 mg/kg with a maximum dose of 200 mg per cycle.

During the annual breast cancer symposium, key findings in this heavily pre-treated patient population were presented by Jennifer M. Specht, MD, a medical oncologist who specializes in treating women with breast cancer at the Seattle Cancer Care Alliance.

These findings based on response assessed per RECIST v1.1 in which patients with stable disease (SD) or better can continue treatment until disease progression or intolerable toxicity, confirmed that among the 60 efficacy-evaluable patients with metastatic TNBC, the objective response rate (ORR) was 25%, representing all partial responses (PR).

In addition, the findings showed that the clinical benefit rate (CBR), defined as patients achieving complete response (CR) or PR of any duration, plus patients achieving stable disease (SD) lasting at least 24 weeks, was 28%. Furthermore:

  • Of the 17 efficacy-evaluable patients treated at the recommended dose, 29% achieved an objective response (confirmed and unconfirmed), and the CBR was 29%.
  • The median progression-free survival (PFS) and median duration of response (DOR) for patients treated across all dose levels were 11 weeks and 13.3 weeks, respectively. In 19 patients treated at the recommended dose, the median PFS was 12.1 weeks, and the median DOR was 17.4 weeks.
  • At the recommended dose, ladiratuzumab vedotin was generally well-tolerated and most adverse events were Grade 1/2.
  • Of the 81 patients treated in the study, peripheral neuropathy events occurred in 16 patients (19.8%) and were generally low grade (Grades 1/2) and manageable. Seven patients discontinued treatment due to adverse events.
  • Grade 3/4 adverse events included neutropenia and anemia. The Grade 3/4 incidence of neutropenia at the 2.5 mg/kg dose was 38.7 percent. As previously reported, two patients experienced febrile neutropenia, and there was one treatment-related death due to presumed sepsis among patients who received doses greater than 200 mg. No other treatment-related deaths occurred in the study.

Enrollment continues for patients with metastatic TNBC at the recommended dose of 2.5 mg/kg, with a maximum dose of 200 mg per cycle.


Last Editorial Review: December 18, 2017

Featured Image: Attendees during general session, on Wednesday December 6, 2017, during the San Antonio Breast Cancer Symposium (SABCS) being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. This year is the 40th Anniversary of the meeting where over 7,500 physicians, researchers, patient advocates and healthcare professionals from over 90 countries attended the meeting which features the latest research on breast cancer treatment and prevention.Courtesy: © 2010 – 2017 MedMeetingImages/Todd Buchanan. Used with Permission.

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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.

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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Seattle Genetics and Astellas Pharma Evaluate Enfortumab Vedotin as Monotherapy in Locally Advanced or Metastatic Urothelial Cancer Previously Treated with a Checkpoint Inhibitor

Seattle Genetics and Astellas Pharma today confirmed dosing the first patient in EV-201, a registrational phase II clinical trial of enfortumab vedotin as a monotherapy for patients with locally advanced or metastatic urothelial cancer who have been previously treated with checkpoint inhibitor or CPI therapy.[1]

Urothelial cancer is most commonly found in the bladder. According to the American Cancer Society, approximately 79,000 people in the U.S. will be diagnosed with bladder cancer during 2017 and almost 17,000 will die from the disease. Outcomes are poor for patients diagnosed with metastatic disease, with a five-year survival rate of five percent.


Our decision to move forward with this registrational trial is based on the results of our ongoing Phase I study… [with] enfortumab vedotin…


One potential treatment option being investigated in a number of clinical trials is enfortumab vedotin, an investigational antinody-drug conjugate or ADC composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent called Monomethyl Auristatin E, also known as MMAE. The drug uses Seattle Genetics’ proprietary, industry-leading linker technology.

Enfortumab vedotin targets Nectin-4, a cell adhesion molecule identified as an ADC target by Agensys, an affiliate of Astellas, which is expressed on many solid tumors.

Nectin-4 is highly expressed in urothelial cancers, particularly in bladder cancer. Preclinical data demonstrate that enfortumab vedotin binds to Nectin-4 on cancer cells and releases the cell-killing agent into these target cells upon internalization.

EV-201
The EV-201 trial is designed to assess the antitumor activity and safety of enfortumab vedotin to support potential registration under the U.S. Food and Drug Administration’s (FDA) accelerated approval regulations.

Schematic 1.0: NCT03219333 (EV-201) is a clinical trial designed to evaluate how an experimental drug (enfortumab vedotin) affects patients with cancer of the urinary system (urothelial cancer). This type of cancer includes cancer of the bladder, renal pelvis, ureter or urethra that has spread to nearby tissues or to other areas of the body. This clinical trial will enroll patients who were previously treated with a kind of anticancer drug called an immune checkpoint inhibitor (CPI). Some CPIs have been approved for the treatment of urothelial cancer. Furthermore, this study will evaluate if the Locally Advanced or Metastatic Urothelial Cancer shrinks with treatment. This study will also look at the side effects of the drug. A side effect is a response to a drug that is not part of the treatment effect.

“Our decision to move forward with this registrational trial is based on the results of our ongoing Phase I study, and we look forward to future clinical development milestones for enfortumab vedotin,” noted Astellas President and Chief Executive Officer Yoshihiko Hatanaka,

“Locally advanced or metastatic urothelial cancers are often aggressive and treatment-resistant. Treatment options are limited for those many patients who do not respond to chemotherapy and checkpoint inhibitors, or CPIs. In addition, there are no FDA-approved therapies for patients who progress following CPI treatment,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“Initiation of this pivotal phase 2 trial of enfortumab vedotin is a significant advance toward our goal of providing a new treatment option for locally advanced or metastatic urothelial cancer,” Drachman.

Study design
The primary endpoint of the single-arm, open-label trial is confirmed objective response rate or ORR, per independent review. Secondary endpoints include assessments of overall survival, progression free-survival, safety and tolerability. The study will enroll approximately 120 patients at multiple centers globally, and enfortumab vedotin will be administered three of every four weeks for the duration of treatment.

“The initiation of the EV-201 clinical trial demonstrates our continued commitment to patients living with locally advanced or metastatic urothelial cancer,” said Steven Benner, M.D., Senior Vice President and Global Therapeutic Area Head, Oncology Development at Astellas.

“Our decision to move forward with this registrational trial is based on the results of our ongoing Phase I study, and we look forward to future clinical development milestones for enfortumab vedotin.”

Seattle Genetics and Astellas Pharma also plan to initiate a combination trial of enfortumab vedotin with CPI therapy in late 2017.

Astellas and Seattle Genetics started their ADC-development collaboration in January 2007 and expanded it in November 2009. Under the collaboration, the companies are co-developing and have options to globally co-commercialize enfortumab vedotin.


Last Editorial Review: October 10, 2017

Featured Image: Using fire as a symbol of cancer of the internal organs, including bladder, liver, and kidneys. Courtesy: © 2017. Fotolia. Used with permission.

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Phase II Trial of Tisotumab Vedotin in Advanced Cervical Cancer Provides Opportunity for Accelerated Approval

Genmab and Seattle Genetics confirmed their decision to start a Phase II study of tisotumab vedotin in patients with recurrent and/or metastatic cervical cancer. The study could provide the basis for a regulatory application for approval.

Cervical cancer originates in the cells lining the cervix, which connects the uterus to the birth canal. About 13,000 women are expected to be diagnosed with cervical cancer in the US in 2017, with an estimated 4000 deaths.[1] Globally, it was estimated that 527,000 people would be diagnosed and 265,000 would die from the disease in 2012, the vast majority of these patients being in the developing world.[2] Routine medical examinations and the human papillomavirus (HPV) vaccine have had a positive impact on the incidence of cervical cancer in the developed world.


Based on promising data from the Phase I/II clinical trial of tisotumab vedotin in recurrent and/or metastatic cervical cancer and feedback from the U.S. Food and Drug Administration (FDA) on the planned trial…  we’re advancing the investigationl agent into a potentially registrational study …  [for] patients with [a] highly unmet medical need…


Despite these advances, women are still diagnosed with cervical cancer, which can have a devastating impact, particularly in the recurrent or metastatic setting. Standard therapies for previously treated recurrent/metastatic cervical cancer generally result in response rates of less than 15% and a median overall survival of 6 to 8 months.[3][4][5][6][7][8][9][10]

Investigational treatment
Tisotumab vedotin is an investigational antibody-drug conjugate or ADC being evaluated for the treatment of cervical cancer and consists of a tissue factor (TF)-targeted human antibody developed by Genmab, an international biotechnology company specializing in the creation and development of differentiated antibody therapeutics for the treatment of cancer.

The tissue factor targeting antibody is linked to the cell-killing agent monomethyl auristatin E, also known as MMAE. The drug further utilizes a cleavable linker developped by Seattle Genetics.

Tissue factor is a protein expressed on a broad range of solid tumors and is involved in tumor signaling and angiogenesis. Based on its high expression on many solid tumors and its rapid internalization, TF was selected as a target for an ADC approach.

Trial design
The Phase II trial is single arm and includes about 100 patients with recurrent or metastatic cervical cancer who relapsed or progressed after standard of care treatment.

The companies plan to start enrolling patients by the first half of 2018.

The single arm, multicenter Phase II study (GCT1015-04) of tisotumab vedotin monotherapy is expected to enroll about 100 patients with recurrent or metastatic cervical cancer who have experienced disease progression on or after platinum containing chemotherapy and who have received or are ineligible for bevacizumab. The primary endpoint of the study is overall response rate (ORR) as assessed by independent review of RECIST v1.1 criteria. The main secondary endpoints are duration of response (DoR) and safety.

Unmet medical need
“We are very pleased to see the clinical development of tisotumab vedotin progress in patients with cervical cancer – an area with a strong unmet medical need. The study provides an opportunity for accelerated registration. We look forward to the continuing development of this promising first-in-class antibody-drug conjugate,” said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

“Standard therapies for previously treated recurrent and/or metastatic cervical cancer generally result in response rates of less than 15% and a median overall survival of six to eight months,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“Based on promising data from the Phase I/II clinical trial of tisotumab vedotin in recurrent and/or metastatic cervical cancer and feedback from the U.S. Food and Drug Administration (FDA) on the planned trial, we and Genmab are advancing the program into a potentially registrational study for these patients with high unmet medical need.”

Tisotumab vedotin is being co-developed by Genmab and Seattle Genetics, under an agreement in which the companies share all future costs and profits for the product on a 50:50 basis.


Last Editorial Review: October 10, 2017

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Seattle Genetics to Co-develop Tisotumab Vedodin with Genmab for the Treatment of Recurrent Cervical Cancer and Other Solid Tumors

Genmab, an international biotechnology company headquartered in Copenhagen, Denmark, and Seattle Genetics, confirmed that Seattle Genetics has exercised its option to co-develop tisotumab vedotin. The companies originally entered into a commercial license and collaboration agreement in October 2011 under which Seattle Genetics had the right to exercise a co-development option for tisotumab vedotin at the end of Phase I clinical development.

Tisotumab vedotin is an  antibody-drug conjugate (ADC) composed of a human antibody that targets or binds to tissue factor or TF and Seattle Genetics’ ADC technology that utilizes a cleavable linker and the cytotoxic drug monomethyl auristatin E (MMAE).  Tissue Factor is a protein involved in tumor signaling and angiogenesis. Based on its high expression on many solid tumors and its rapid internalization, TF was selected as a target for an ADC approach. Tisotumab vedotin is in Phase I/II clinical studies for the treatment of recurrent cervical cancer and has additional potential for the treatment of other solid tumors.[1]


“Together … we’re looking forward to advancing tisotumab vedotin for the treatment of solid tumors.”


Going forward, Genmab and Seattle Genetics will co-develop and share all future costs and profits for tisotumab vedotin on a 50:50 basis.

“The combination of Genmab’s differentiated HuMax®-TF antibody and Seattle Genetics’ clinically-validated ADC technology has resulted in encouraging preliminary data for tisotumab vedotin in selected solid tumors. We very much look forward to working with Seattle Genetics to further develop this exciting first-in-class ADC product,” said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

Promising data
“Our ADC partnership with Genmab has generated promising Phase I/II data for tisotumab vedotin in patients with recurrent cervical cancer. As Seattle Genetics opts into co-development of this clinical program, we add another potential product to our strong pipeline,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“Together with Genmab, we look forward to advancing tisotumab vedotin for the treatment of solid tumors,” Siegall added.

Manageable safety
Preliminary data from the ongoing Phase I/II study of tisotumab vedotin in solid tumors (GEN701) were announced in June 2017, demonstrating antitumor activity and manageable safety in recurrent cervical cancer patients. This announcement can be found here. Updated preliminary data from the Phase I/II study will be presented in an oral presentation during the upcoming at the annual meeting of the European Society for Medical Oncology (ESMO) to be held in Madrid, Spain, September 8-12, 2017.

Collaboration
In October 2011, Genmab and Seattle Genetics entered into a commercial license and collaboration agreement for ADCs. Under the agreement, Genmab was granted rights to utilize Seattle Genetics ADC technology with its HuMax®-TF antibody. In turn, Seattle Genetics was granted rights to exercise a co-development and co-commercialization option at the end of Phase I clinical development for tisotumab vedotin.

With today’s news Seattle Genetics exercises its option to co-develop tisotumab vedotin and the companies will share all future costs and profits for the product on a 50:50 basis.

As part of the agreement, Seattle Genetics will be responsible for commercialization activities in the US, Canada, and Mexico, while Genmab will be responsible for commercialization activities in all other territories around the world. Each party has the option to co-promote by employing up to 40% of the sales effort in the other party’s territories.


Last Editorial Review: August 29, 2017

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Brentuximab Vedotin Approved by Health Canada for Post-ASCT Consolidation Treatment of Patients with Hodgkin Lymphoma

Health Canada, the federal department responsible for helping Canadians maintain and improve their health, has issued a non-conditional marketing authorization for use of brentuximab vedotin (Adcetris®; Seattle Genetics) as post-autologous stem cell transplant (ASCT) consolidation treatment of patients with Hodgkin lymphoma (HL) at increased risk of relapse or progression.

In 2013 Health Canada granted brentuximab vedotin approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL, and non-conditional approval for post-ASCT consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.

Brentuximab vedotin is an antibody-drug conjugate or ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells.

The drug is used in the treatment of lymphoma, a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

Fig 1.0: The AETHERA Trial is a Phase III Study of brentuximab vedotin, also known as SGN-35, in Patients at High Risk of Residual Hodgkin Lymphoma Following Stem Cell Transplant. PFS follow-up (year 2) included continued monitoring with scans at 18 and 24 months and quarterly clinical assessments. Patients in this trial who experienced disease progression per investigator during the study were unblinded and could receive brentuximab vedotin as part of a separate trial.

AETHERA trial
The newly approved indication is based on positive results from the phase III AETHERA clinical trial. [1] Brentuximab vedotin previously received approval with conditions in Canada for two lymphoma indications: HL patients who relapse after ASCT or relapse after at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates; and for systemic anaplastic large cell lymphoma (sALCL) patients who relapse after at least one multi-agent chemotherapy regimen.

“With this expanded brentuximab vedotin label, physicians and eligible patients in Canada will have further access to this important therapeutic option for treating Hodgkin lymphoma,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“This is one of several brentuximab vedotin regulatory milestones during 2017 towards our goal of expanding its availabilty globally to patients in need. We recently submitted a supplemental Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for brentuximab vedotin approval in cutaneous T-cell lymphoma based primarily on our phase III ALCANZA clinical trial, and we plan to submit a supplemental BLA to the FDA for brentuximab vedotin in frontline Hodgkin lymphoma based on the positive phase III ECHELON-1 clinical trial. We plan to follow up with submissions to Health Canada for indications in these settings,” Siegall added.

Brentuximab vedotin is currently not approved for use in Cutaneous T-Cell Lymphoma (CTCL) or frontline Hodgkin lymphoma.


Last editorial review: July 25, 2017

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