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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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Denintuzumab Mafodotin: Testing Novel Regimens for Frontline and Relapsed DLBCL

Highlighted clinical data with denintuzumab mafodotin (SGN-CD19A; 19A; Seattle Genetics) in B-cell malignancies, including diffuse large B-cell lymphoma, also known as DLBCL, and B-lineage acute lymphocytic leukemia or B-ALL, presented at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in Orlando, Florida, December 5-8, 2015, supports further clinical evaluation in a randomized phase of the novel trial drug.

During the 57th ASH annual meeting, preclinical data from another new antibody-drug conjugate or ADC program called SGN-CD19B in B-cell malignancies was also featured in an oral presentation. About 85% of non-Hodgkin lymphomas or NHLs are B-cell lineage.  NHL is categorized into indolent (low-grade) or aggressive, including diffuse large B-cell lymphoma or DLBCL. DLBCL is the most common type of NHL. According to the American Cancer Society, more than 71,000 cases of NHL were to be diagnosed in the United States during 2015 and more than 19,000 people would die from the disease.

Photo: Main entry of the 57th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in Orlando, Florida, December 5-8, 2015.

Acute lymphoblastic leukemia, also called acute lymphocytic leukemia or ALL, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. In ALL, lymphoblasts, which are malignant, immature white blood cells, multiply and crowd out normal cells in the bone marrow. ALL is the most common type of cancer in children and in about 80% to 85% of these children with ALL, the leukemia starts in B cells.

According to the American Cancer Society, more than 6,000 people were diagnosed with ALL during 2015, and more than 1,400 would die from the disease. And while most cases of ALL occur in children, most deaths from the disease (about 4 out of 5) occur in adults. One reason is that, according to the American Cancer Society, children may do better because of differences in childhood and adult ALL in the disease itself, differences in treatment (children can often handle aggressive treatment better than adults), or some combination of these factors.

Antibody-drug conjugates
The two antibody-drug conjugates or ADCs, denintuzumab mafodotin (SGN-CD19A; 19A) and SGN-CD19B, both target CD19, a protein broadly expressed across all subtypes of B-cell malignancies, and utilize two of Seattle Genetics’ proprietary payloads, the synthetic cell-killing agent monomethyl auristatin F (MMAF) and a pyrrolobenzodiazepine (PBD) dimer, respectively.  One of the unique features of these novel agents is that they are designed to be stable in the bloodstream, and to release its cytotoxic agent upon internalization into CD19-expressing tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing the antitumor activity.

Seattle Genetics has initiated the first of two planned phase II trials of denintuzumab mafodotin in DLBCL and plans to advance SGN-CD19B into a phase I trial in 2016.

Further investigation
“Data presented at [57th Annual Meeting of the American Society of Hematology] from our 19A phase I trial in non-Hodgkin lymphoma show encouraging objective response rates, particularly in relapsed DLBCL patients, and a tolerability profile that we believe supports further investigation as part of novel regimens. Based on these data, we recently initiated a phase II trial in relapsed DLBCL, and plan to initiate a phase II trial in frontline DLBCL during 2016,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“CD19 is an attractive target for NHL, and there is a clear need for potent, safe and convenient therapies that can be used to improve outcomes for patients,” Drachman continued.

With more than 15 years of experience and innovation, Seattle Genetics is leading the development of antibody-drug conjugates, a technology designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. More than 25 ADCs in clinical development utilize Seattle Genetics’ proprietary ADC technology.

Denintuzumab Mafodotin in B-Lineage Non-Hodgkin Lymphoma
During the 57th ASH Annual Meeting data were reported from 62 patients with relapsed or refractory NHL, including 54 patients with DLBCL, five patients with mantle cell lymphoma and three patients with grade 3 follicular lymphoma. Of the 62 patients, 37 patients (60%) were refractory to their last therapy and 25 patients (40%) were relapsed. Sixteen patients (26%) had received a prior autologous stem cell transplant. The median age of patients was 65 years. [1]

The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and evaluate the safety and tolerability of denintuzumab mafodotin. In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this study, patients receive denintuzumab mafodotin either every three weeks or every six weeks. Patients with stable disease or better are eligible to continue treatment with denintuzumab mafodotin.

The key findings from an oral presentation by Craig Moskowitz, M.D. Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, confirm that the maximum tolerated dose of the trial drug was not exceeded after escalating to 6 milligrams per kilogram (mg/kg) every three weeks.

In this trial, which included 60 patients evaluable for response, 23 patients (38%) achieved an objective response (OR), including 14 patients (23%) with a complete remission and nine patients (15%) with a partial remission. Thirteen patients (22%) achieved stable disease and 24 patients (40%) had disease progression.

Antitumor activity
The researchers noted that the antitumor activity appeared to be higher in relapsed patients. Of the 25 relapsed patients, 15 patients (60%) achieved an objective response, including 10 patients (40%) with a complete remission. In the 23 relapsed patients who responded, median duration of response was 47.1 weeks. Among all relapsed patients, median progression-free survival was 25.1 weeks and median overall survival was 56.7 weeks.

Adverse events
The most common adverse events of any grade occurring in more than 15 percent of patients were blurred vision (63%); dry eye (53%); fatigue, keratopathy and photophobia (39% each). Ocular symptoms were reported in more than 70% of patients. Symptoms were mostly Grade 1/2 and were managed with steroid eye drop treatment and dose modifications. Eighty-eight percent of patients with Grade 3 or 4 keratopathy experienced improvement and/or resolution within a median of five weeks.

B-Lineage Acute Leukemia
Data were reported from 72 adult patients with relapsed or refractory B-ALL and highly aggressive lymphomas, including B-cell lymphoblastic lymphoma (B-LBL) and Burkitt lymphoma. The median age of adult patients was 45 years and the median number of prior systemic therapies was two, with 20 patients (28%) having received a prior allogeneic stem cell transplant. [2]

The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and to evaluate the safety of denintuzumab mafodotin (SGN-CD19A). In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this dose-escalation study, patients received denintuzumab mafodotin in Schedule A (40 patients) at 0.3 to 3 mg/kg weekly or Schedule B (32 patients) at 4 to 6 mg/kg every three weeks.  Key findings of this trial show that of the 56 B-ALL adult patients evaluable for response, six patients (19%) treated weekly achieved a composite complete remission (complete remission or complete remission with incomplete platelet or blood recovery) and nine patients (38%) treated every three weeks achieved a composite complete remission. The median duration of response was 27 weeks. Fifty-four percent of patients across both schedules achieved cytoreduction of greater than 50%.

Furthermore, trial results show that in the ten patients with Philadelphia chromosome positive (Ph+) B-ALL, five patients (50%) achieved a complete remission and one patient (10%) had a partial remission. Ph+ B-ALL represents 20 to 30% of adult patients and carries a dismal prognosis, with higher rates of relapse and lower overall survival.

Maximum tolerated dose and adverse events
The maximum tolerated dose or MTD, the highest dose of the trial drug that did not cause unacceptable side effects established by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found, was not reached in patients treated weekly but was identified at 5 mg/kg in patients treated every three weeks.

The most common adverse events of any grade occurring in 25% or more of patients treated weekly (40 patients) or every three weeks (32 patients), respectively, were nausea (63 and 41%), fatigue (58 and 47%), fever (55 and 50%), headache (45 and 38%) and anemia (43 and 22%).

In the study, 43 patients (60%) developed ocular symptoms, of which 91% were Grade 1/2. These included blurred vision (39%), dry eye (25%) and photophobia (19%). Ocular symptoms were managed with steroid eye drop treatment and dose modifications. Keratopathy was observed in 34 patients, of whom 22 patients had Grade 3/4 events. The majority of patients with Grade 3/4 events had improvement or resolution with a median time of approximately four weeks.

Trials with denintuzumab mafodotin (SGN-CD19A) phase I clinical trials are ongoing. Separately, a randomized phase II trial has recently initiated evaluating 19A in combination with R-ICE chemotherapy for second-line DLBCL. In addition, a phase 2 clinical trial in frontline DLBCL is planned to begin in 2016.

SGN-CD19B
A preclinical analysis evaluated the activity of SGN-CD19B, a new ADC consisting of an anti-CD19 antibody attached to a highly potent DNA binding agent called a PBD dimer, in multiple B-cell malignancy models. Data to be presented in an oral session demonstrate that SGN-CD19B exhibits antitumor activity against a broad panel of CD19-expressing B-cell malignancies, inducing durable tumor regressions and improved survival in multiple preclinical models of NHL and B-ALL. Based on these data, a phase 1 clinical trial evaluating SGN-CD19B in NHL is planned to start in 2016. [3]

Dramatic advances
“[These and other] studies presented [during the 57th American Society of Hematology (ASH) Annual Meeting and Exposition] showcase dramatic advances that are revolutionizing the way we treat patients with blood cancers, as well as the promise of novel approaches yet to come,” noted Gary Schiller, M.D., Professor of Medicine in the Division of Hematology/Oncology at the University of California, Los Angeles School of Medicine.

“We are seeing how scientific discoveries in the lab are translating into real, positive clinical impact. Patients, especially those with challenging diseases, can be heartened by the tremendous expansion of options and new therapeutic approaches,” Schiller concluded.


Last Editorial Review: December 6, 2015

Photo & Featured Image: 57th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in Orlando, Florida, December 5-8, 2015.  Courtesy: © Sunvalley Communication, LLC. Used with permission.

Copyright © 2015 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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Phase II Trial of Denintuzumab Mafodotin Combination Therapy in Relapsed or Refractory Diffuse Large B-cell Lymphoma Intated

A randomized phase II clinical trial of denintuzumab mafodotin, also known as SGN-CD19A (SGN-19A), in combination with the second-line salvage regimen of rituximab (Rituxan®; Genentech/Biogen), ifosfamide, carboplatin and etoposide (RICE), for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), has been initiated by researchers at Seattle Genetics, a biotechnology company leading the field in developing antibody-drug conjugates or ADCs.

The new trial is based on data from phase I trial in B-cell Non-Hodgkin Lymphoma demonstrating that denintuzumab mafodotin is generally well tolerated and shows encouraging activity with durable responses in heavily pre-treated patents with B-cell non-Hodgkin lymphoma.[1]

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. The two major categories of lymphoma include Hodgkin lymphoma and non-Hodgkin lymphoma.

Non-Hodgkin lymphoma represents a diverse group of cancers that develop in the lymphatic system and are characterized by uncontrolled growth and accumulation of abnormal lymphocytes. Lymphocytes are a type of blood cells that are responsible for defending the body against infection. The most common forms of non-Hodgkin lymphoma are diffuse large B-cell lymphoma or DLBCL (an aggressive subtype) and follicular lymphoma (an indolent subtype).

Diffuse large B-cell lymphoma is the most common type of aggressive non-Hodgkin lymphoma. The new study is intended to evaluate the activity and safety of the combination regimen compared to RICE alone.

Reducing toxic effects of chemotherapy
Denintuzumab mafodotin is a novel antibody-drug conjugate targeting CD19, a protein expressed uniformly on almost all B-cell malignancies. The drug is composed of a humanized anti‑CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. The ADC is designed to be stable in the bloodstream and release its cytotoxic agent upon internalization into CD19-expressing cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects associated with traditional chemotherapy while enhancing antitumor activity.

“The only curative option for patients with diffuse large B-cell lymphoma, or DLBCL, who relapse after initial treatment is an intensive salvage regimen with the goal of achieving the best possible response prior to autologous stem cell transplant. Those who are transplanted in PET-negative complete remission have the best outcomes. Currently, only 50% of DLBCL patients are able to proceed to a transplant following treatment with any of the currently available salvage treatment regimens, representing a significant need to identify more effective treatment options,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“In relapsed DLBCL patients in a phase I clinical trial, we have observed an objective response rate over 50 percent with denintuzumab mafodotin monotherapy and a tolerability profile that is well suited to combination regimens. Our preclinical data suggest that combining denintuzumab mafodotin with RICE may result in synergistic activity, potentially leading to improved treatment outcomes in relapsed or refractory DLBCL patients,” Drachman Continued.

Trial design
In this phase II randomized, open-label, multi-center clinical trial, approximately 150 relapsed/refractory DLBCL or grade 3B follicular lymphoma patients who are eligible for an autologous stem cell transplant (ASCT) will be randomized to receive RICE either with or without denintuzumab mafodotin every three weeks for three cycles. The primary endpoint is to compare the complete remission rates between the two study arms. Secondary endpoints include safety of the combination regimen, progression-free survival, overall survival and the number of patients who are able to undergo autologous transplant.

At the 2014 annual meeting of the American Society of Hematology (ASH) data were presented from an ongoing phase I trial of relapsed/refractory aggressive non-Hodgkin lymphoma patients who received single-agent denintuzumab mafodotin every three weeks.

Trial results
Of the 51 evaluable patients, including 45 DLBCL patients, the objective response rate across all dose levels was 35%, including 20% complete remissions and 16% partial remissions. In the subset of patients who had relapsed disease, the objective response rate was 55%, including 32% complete remissions and 23% partial remissions. The most common adverse events of any grade occurring in more than 25% of patients were blurred vision (60%), dry eye (46%), fatigue (38%), constipation (33%) and keratopathy (31%). Ocular symptoms and corneal findings were superficial, generally reversible, and were managed with steroid eye drop treatment and dose modifications. The majority of affected patients experienced improvement and/or resolution at last follow up. Furthermore, no significant myelosuppression or peripheral neuropathy were observed, suggesting that denintuzumab mafodotin may be well tolerated in combination with multi-agent chemotherapy.


Last Editorial Review: October 29, 2015

Photo: Young female scientist microscoping on hi-tec fluorescent microscope. . Health care professional in hes working environment. Courtesy: Fotollia. Used with permission.

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