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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.

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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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Antibody-drug Conjugates: Technologies and Global Markets

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


Last editorial review: July 20, 2017

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PEGS Boston 2017: Catalent Biologics Advances Antibody-Drug Conjugate Development

Catalent Pharma Solutions, the leading global provider of advanced delivery technologies and development solutions for drugs, biologics and consumer health products, today announced that David Rabuka, Ph.D, Global Head of Research and Development, Chemical Biology, Catalent Biologics, will be presenting at the upcoming 7th Protein and Antibody Engineering Summit (PEGS Boston), to be held at the Seaport World Trade Center, Boston, Massachusetts, on May 1 – 5, 2017.

On Wednesday, May 3rd Rabuka, is expected to present during the ‘Antibody-Drug Conjugates I: New Targets, Payloads and Alternative Formats’ conference track. His presentation discusses the latest advances in developing antibody-drug conjugates using Catalent’s SMARTag® Technology.

In the presentation, Rabuka will examine the growth of antibody-drug conjugates in clinical trials and pre-clinical development following on from the successes of the approved antibody-drug conjugates drugs brentuximab vedotin (Adcetris™; Seattle Genetics/Takeda) and ado-trastuzumab emtansine (Kadcyla™; Genentech/Roche). He will discuss how innovations in conjugation chemistry and linker technologies suggest further opportunities in the development of antibidy-drug conjugates, and review pre-clinical studies using Catalent’s SMARTag technology platform, which enables precise, programmable, site-selective chemical protein modification.

Analytical services
In addition, Anne Marie Rogan, Senior Associate Scientist at Catalent Biologics’ analytical services will be showcasing expert posters on the use of LC-MS to monitor levels of oxidation and deamidation in proteins for release and stability. Finally, Luke Deters, Senior Manager, Large Molecule Analytical Chemistry will present a poster discussing “quantitation and characterization of polysorbate-80 by HPLC and charged aerosol detection.

SMARTag® Technology
Catalent’s proprietary SMARTag site-specific protein-modification and linker technologies were originally developed by Redwood Bioscience to enable the generation of homogenous bioconjugates engineered to enhance potency, safety and stability. The technology employs natural post-translational modifications found in human cells to create one or more aldehyde tags at designated sites on protein molecules. These chemical “handles’’ are then stably conjugated to payloads (e.g. cytotoxic or effector) to prevent their systemic release. The SMARTag platform provides precise payload positioning, stable, site-specific conjugation and defined stoichiometry of drug–protein ratios. The control afforded by the technology enables identification of superior drugs from libraries of differentially designed conjugates.

Catalent acquired Redwood Bioscience in 2014.


Disclosure: David Rabuka, Ph.D, is a member of the editorial advisory board of ADC Review | Journal of Antibody-drug Conjugates.

Last Editorial Review: April 27, 2017

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Improving Outcomes in the Treatment of Breast Cancer (Video)


Over the last 25 years, there has been an explosion of new and vitally important, anticancer drugs.

The development of these promising new therapeutic agents is generally based on preclinical and clinical research. In many cases, this research has become prohibitively expensive. And only a relatively few investigational drugs have reached the market and successfully improved clinical outcomes in the treatment of patients with cancer and hematological malignancies. In the development of new therapies, the traditional clinical trial process of determining which drugs will ultimately benefit patients is long and expensive.


“The I-SPY Trial Program integrates and links Phase I, Phase II and eventually Phase III clinical oncology trials to build a pipeline of novel anticancer agents…”


Over the last few decades scientists have tried to change – and improve – the way clinical trials are conducted. Their purpose… Improving the process and improving the way novel pharmaceutical drugs are being developed. But it still takes many years and huge investments to successfully bring a new drug to market.

But despite their efforts there is still a huge unmet medical need.

While there are many novel drugs being developed to help improve the outcome and improve survival, resources are limited. Optimal use of resources requires better understanding of cancer biology, the identification of novel therapeutic targets, and the ability to address inefficiencies in the cancer clinical trials system. This may especially be so in how we treat women with metastatic, high risk, breast cancer.

Based on the current limitations in how we conduct clinical trials, scientists of The Biomarkers Consortium, at the Foundation for the National Institutes of Health, are changing the way new anticancer drugs are being developed.

The Foundation’s unique and groundbreaking, re-engineered approach to clinical trials is the I-SPY Clinical Trial. This trial represents an unprecedented and streamlined method in developing new anticancer drugs. Using breast cancer treatment as a model – the I-SPY TRIALs are designed to significantly reduce the overall cost, time, and number of patients required to bring innovative anticancer agents to the right patient at the right time – and do this faster.

The I-SPY Trial Program integrates and links Phase I, Phase II and eventually Phase III clinical oncology trials to build a pipeline of novel anticancer agents. As a result, the new trial program accelerates the process of identifying a subset of high risk breast cancer patients that will directly benefit from these novel agents.

Among the targeted drugs being investigated in the I-SPY 2 trail are antibody-drug conjugates or ADCs. Antibody-drug Conjugates are part of a new wave of targeted antibody-based products. They are novel, innovative agents at the cutting edge of oncology and hematology.

During the Annual Meeting of the American Association of Cancer Research, held – April 16 – 20, 2016, in New Orleans, we sat down with Doctor Angela DeMichele, Professor of Medicine and Epi-demi-ology at the Perelman School of Medicine at the University of Pennsylvania.

We asked Doctor DeMichele a number of questions about a specific part of the I-SPY-2 trial in which researchers investigated a particular antibody-drug conjugate and how a combination of drugs, including antibody-drug conjugates, can bring a substantially greater proportion of patients to the primary endpoint of pathological complete response or PCR, an outcome in which, following neoadjuvant therapy, residual invasive cancer is detected in the breast tissue and lymph nodes during surgery.

And we asked her about the benefit of targeted therapy and how novel drugs like antibody-drug conjugates play a role.


Last Editorial Review: December 30, 2016

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

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Anti-HER2 ADC SYD985 to be Evaluated in Expanded Cohort of HER2+ Metastatic Breast Cancer Patients

Dutch pharmaceutical company Synthon Biopharmaceuticals has initiated the second part of an ongoing phase I clinical trial with its investigational anti-HER2 antibody-drug conjugate or ADC, SYD985.

HER2, which is targeted by SYD985, is a member of the human epidermal growth factor (HER) family of transmembrane tyrosine kinases which, as a result of their significant role in the pathogenesis of various cancer types, has been of considerable interest in oncology. [1]

Researchers at Synthon are investigating SYD985 in a clinical trial called SYD985.001. The trial is a two part first-in-human phase I study designed evaluate the safety, pharmacokinetics and efficacy in patients with histologically-confirmed, locally advanced or metastatic tumors. This includes patients who have progressed on standard therapy or for whom no standard therapy exists. [2]

During the part I, dose escalation, study, patients with solid tumors of any origin were enrolled. Initial results of this part of the trial were presented at the European Cancer Congress (ECC) in Vienna, Austria, in September 2015 [3][4]

For the extended cohorts, the second part of the study, enrollment is focused at patients with breast or selected non-breast tumors with demonstrated HER2 expression and measurable disease lesions as per protocol defined criteria. In this part, researchers will enroll 48 additional heavily pre-treated patients with HER2+ breast cancer. This marks an important next step in the development of SYD985, the frontrunner of Synthon’s duocarmycin-based ADC platform.

Platform technology
Antibody-drug conjugates are designed to combine the specificity of antibodies directed against tumor-associated targets with potent cytotoxicity. Upon internalization, the antibody-bound cytotoxins are released intracellularly, leading to programmed tumor cell death.

While the cytotoxins used in the majority of advanced programs in the field prevent tubulin polymerization during cell division, Synthon’s differentiating linker-drug technology − applying valine-citrulline-seco- DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA) − is based on synthetic duocarmycin analogs, which bind to the minor groove of DNA and subsequently cause irreversible alkylation of DNA. This disrupts the nucleic acid architecture, which eventually leads to tumor cell death.

Duocarmycins are able to exert their mode of action at any phase in the cellular cycle, whereas tubulin binders will only attack tumor cells when they are in a mitotic phase. Growing evidence suggests that DNA damaging agents, such as duocarmycins, are more efficacious in tumor cell killing than tubulin binders, particularly in solid tumors.

Although based on natural products, Synthon’s proprietary linker-drug technology uses fully synthetic duocarmycin analogs. The unique design of the selectively cleavable linker connecting the antibody to the duocarmycin drug leads to high stability in circulation, and induces efficient release of the cytotoxin in the tumor. [5]

Preclinical in vitro and in vivo findings
Preclinical in vitro and in vivo findings in a head-to-head comparison of SYD985 and ado-trastuzumab emtansine, also known as T-DM1 (Kadcyla®; Genentech/Roche) have confirmed that the two drugs have similar binding affinities to HER2 and showed similar internalization.

Ado-trastuzumab emtansine consists of the monoclonal antibody trastuzumab conjugated to the cytotoxic maytansine anti-tubulin agent DM1.  In vitro, the two compounds also showed similar potencies and efficacies in HER2 3+ cell lines. [6]

However, in preclinical trials the researchers found that in cell lines with low HER2 expression, SYD985 was 3- to 50-fold more potent than ado-trastuzumab emtansine. Furthermore, the researchers noticed that, in contrast with ado-trastuzumab emtansine, SYD985 efficiently induced bystander killing in vitro in HER2-negative (HER2 0) cells mixed with HER2 3+, 2+, or 1+ cell lines. Bystander killing is one of the possible explanations for the observed difference in antitumor activity between SYD985  and ado-trastuzumab emtansine in low HER2-expressing and/or heterogeneous tumors. [6]

In preclinical studies researchers also found that at pH conditions relevant for tumors, cathepsin-B cleavage showed efficient release of the active cytotoxic payload by SYD985.  In contrast, ado-trastuzumab emtansine did not show the same results.

Improving treatment
Although the introduction of ado-trastuzumab emtansine in clinical practice has brought great improvements for HER2-positive metastatic breast cancer patients, use of ado-trastuzumab emtansine is associated with a number of serious side-effects, most importantly thrombocytopenia, hepato toxicity, and neuropathy (irreversible axonal degeneration). Furthermore, neither trastuzumab nor ado-trastuzumab emtansine are approved for the treatment of human solid tumours and haematological malignancies with moderate or low HER2 expression, i.e. IHC 2+ or 1+ and/or FISH negative HER2 amplification status of the cancer tissue. [7]

More potent in low HER2-expressing cancers
The initial in vitro data suggested that SYD985 is a more potent antibody-drug conjugate in HER2-expressing tumors in vivo, especially in low HER2-expressing and/or in heterogeneous tumors. In line with this, in vivo antitumor studies in breast cancer patient-derived xenograft (PDX) models showed that SYD985 is very active in HER2 3+, 2+, and 1+ models, whereas ado-trastuzumab emtansine only showed significant antitumor activity in HER2 3+ breast cancer PDX models. [6]

Based on these preclinical data, researchers at Synthon concluded that SYD985 offers clinically relevant efficacy in patients with breast cancer with low levels of HER2 expression. This conclusion let study ongoing clinical studies to evaluate the safety SYD985 at different dose levels, to understand how SYD985 is handled by the body and to evaluate the effect of SYD985 in HER2+ cancers.

Phase I dose finding study
In the initial dose-finding part of the SYD985.001 trial, promising results were obtained in 33 cancer patients who were dosed with between 0.3 and 2.4 mg/kg of SYD985 every three weeks. Most noticeably, very high response rates and durable responses were observed in patients whose cancers were refractory to HER2-targeted agents, including trastuzumab (Herceptin®; Genentech/Roche) and ado-trastuzumab emtansine, following treatment with SYD985 at doses from 1.2 mg/kg onwards.

Although data from the dose-finding part – which includes patients with solid tumors of any origin – will continue to be collected, evaluation of the larger cohort of 48 heavily pre-treated breast cancer patients with HER2-positive tumors (i.e. HER2 3+ or FISH-positive) has been initiated.

Clinical evaluation in this heavily pre-treated patient population, whose cancers are refractory to multiple lines of registered HER2-targeting treatments including trastuzumab and ado-trastuzumab emtansine, will continue to collect data on efficacy, safety and tolerability of SYD985 treatment at a starting dose of 1.2 mg/kg.

Data from this cohort will enable researchers at Synthon to design the first pivotal trial with SYD985 as suggested by several national regulatory authorities and subject to an ongoing EMA scientific advice request regarding the most optimal development pathway.

Investigational New Drug Application
Synthon is expected to submit a pre-IND (Investigational New Drug Application) meeting request to the U.S. Food and Drug Administration (FDA) to extend its clinical development program to include U.S. clinical sites under an IND.

“The auspicious data we have already obtained with SYD985 confirms our belief in this potential new HER2-targeting treatment for patients whose cancers have become refractory to currently available anti-HER2-treatments,” noted Jacques Lemmens, founder and CEO of Synthon.

“Encouraged by the enthusiasm of our principal investigators and the regulatory bodies that have been consulted, we are further expediting our efforts to drive this compound forward towards a market authorization. The expanded cohort will provide us with information about the minimum effective dose; a very important parameter in this vulnerable group of patients,” Lemons continued.

Meanwhile, the evaluation in the dose-finding part of the trial continues to further investigate efficacy and safety of repeated treatment cycles.

Existing literature has shown that that HER2 overexpression exist in a subset of patients with non-breast and non-gastric cancers.  As a result, researchers believe in the promise of anti-HER2 targeted therapy in these patients. [1] Hence, following determination of the recommended dose of SYD985 later this year, more patients will be enrolled in this trial, including those with breast cancer with lower HER2 expression (HER2 1+/2+ or FISH-negative) as well as those with gastric, endometrial or bladder cancer.


Last Editorial Review: May 19, 2016

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Clinical Updates Confirming Advances and Meaningful Benefits for Patients

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

Last Editorial Review: May 10, 2016

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

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Growing Drug Development Outsourcing Expected to Increase Demand for Antibody-drug Conjugates

A recent research report published by Technavio, a leading global technology research and advisory company, confirms that the global antibody-drug conjugates (ADC) market will grow at a CAGR of over 41% until 2020.

This report “Global Antibody Drug Conjugates Market 2016-2020,” offers an in-depth analysis of the market in terms of revenue and emerging trends. To calculate the market size, the report considers revenue generated from the sales of currently approved ADCs used to treat cancer.

The importance of ADC is confirmed by the approval of brentuximab vedotin (Adcetris™, Seattle Genetics) and ado-trastuzumab emtansine (Kadcyla™, Genentech/Roche) and the large number of ADCs (>35) currently in clinical trials.[1]

Outsourcing development
“Vendors are increasingly outsourcing parts of their R&D process, such as product characterization testing and toxicology testing, to contract research organizations. Similarly, individual vendors are increasingly outsourcing their manufacturing processes,” Barath Palada, one of Technavio’s lead industry analysts for cardiovascular and molecular disorders.

“This decreases the manufacturing cost of originators, and increases profit margins. It is estimated that close to 70%-80% of antibody-conjugate drugs manufacturing is currently being outsourced, and this trend is expected to positively impact the market over the course of the forecast period,” Palada continued.

According to the report’s authors, some of the other driving forces behind the growth of the global antibody-drug conjugates market include a robust late-stage pipeline, an increase in demand for antibody-drug conjugates and relatively favorable reimbursement policies.

Robust late-stage pipeline
There are many products in the late pipeline stage that are likely be launched during the forecast period. Some of these products include glembatumumab vedotin, also known as CDX-011 or CR011-vcMMAE, an ADC designed to target the glycoprotein NMB (gpNMB) being developed by Celldex Therapeutics and SYD985, an investigational HER2-targeting ADC being developed by Synthon Biopharmaceuticals.

Some molecules are in phase I/II, preclinical, and discovery stages. Brentuximab vedotin is currently under clinical trials for additional indications such as frontline mature T-cell lymphomas, B-cell lymphomas, and CD30-expressing conditions. Experts interviewed by the report’s authors believe that these novel drugs form a strong pipeline for ADCs, and their approval in the forecast period is expected to propel market growth significantly.

Increase in demand
Antibody-drug conjugates have a high affinity for specific disease cells and areas that need treatment. The use of antibody-drug conjugates is expected to grow, and include therapies such as radio immunotherapy and antibody-directed enzyme prodrug therapy. A key advantage of using ADCs is that it brings together better characteristics of both antibodies and cytotoxic chemotherapy. This presents a huge opportunity in terms of targeted drug accumulation in tissues or tumor cells.

Over the next few years many new entrants are expected to enter the market, and increase competition in the market. Rising use of antibodies in drug development is expected to further increase revenues of vendors in the global ADCs market, and contribute to its growth until 2020.

Reimbursement policies
Reimbursement plans such as public reimbursement programs reduce the financial burden of treatment, and thereby benefit patients. The reimbursement status of drugs is dynamic in nature with inter-country variations. Factors such as lack of cost-effectiveness can impede reimbursement coverage. However, increased demand and high cost of cancer drugs are important reasons for these drugs to be included in reimbursement plans.

United States
In the United Stares, the Affordable Care Act (ACA) makes premium-priced drugs for the treatment of diseases available to patients at affordable rates. Many vendors also offer patient assistance programs to make these expensive drugs available to all. For instance, Genentech has initiated reimbursement plans for ado-trastuzumab emtansine, a target-specific drug, through Genentech Access Solutions.

These favorable reimbursement policies will positively impact the global antibody conjugates drugs market until 2020.

The European Commissions has approved ado-trastuzumab emtansine (which is in Europe distributed by Roche), in November 2013. The (European) Committee for Medicinal Products for Human Use (CHMP), on the basis of their quality, safety and efficacy data assessment, considers there to be a favourable benefit-to-risk balance for ado-trastuzumab emtansine. As a result, they recommends the granting of the marketing authorization in all European member states.[2]

However, following this positive guidance, not all European member states decide to reimburse innovative drugs.

Fore example, while retained for use through the UK’s Cancer Drugs Fund, ado-trastuzumab emtansine, was not recommended for routine NHS use by the UK’s National Institute for Health and Care Excellence (NICE), an independent body responsible for driving improvement and excellence in the health and social care system.[3]

“We recognise that [ado-trastuzumab emtansine] has a place in treating some patients with advanced breast cancer and we have been as flexible as we can in making our recommendation. However, the price that the manufacturer is asking the NHS to pay in the long-term is too high,” noted Sir Andrew Dillon, NICE Chief Executive in late 2015.

“Despite a growing public campaign for a fair deal on the cost of important new cancer medicines, it is disappointing that there appears to have been no meaningful attempt … to reconsider [the] price to secure [ado-trastuzumab emtansine]’s long-term future in the NHS, outside of the Cancer Drugs Fund,” Dillon added.

In Ireland, the National Centre for Pharmacoeconomics (NCPE) has also issues a negative reimbursement advice.

As a result of these negative recommendations experts are concerned that pioneering and innovative treatment designed to improves and extends the life of patients with are not made available to patients in the UK and Ireland – and, as a result, novel drugs are being stifled at the earliest stage before they can show their value.

In contrast, in 2014 France’s Transparency Commission of the Higher Authority on Healthcare recommended ado-trastuzumab emtansine for reimbursement.  The judgement was based on the available data from the pivotal Phase III EMILIA trial which demonstrated a statistically significant increase in median OS of ado-trastuzumab emtansine compared to lapatinib + capecitabine. Ado-trastuzumab emtansine also demonstrated an increase in PFS of 2.1 months as well as a reduction in side effects, making it clear that the drug brings important clinical value.  As a result, patients in France have access to this treatments with a reimbursement rate between 65–100%. In a similar vein, the German Institute for Quality and Efficiency in Health Care (IQWiG) approved the drug for reimbursement.[5]

Consequences
The bad news for large numbers of Europeans living in countries that do not reimburse, and as a result, limit access to newly patented – approved – medicines such as ado-trastuzumab emtansine,  is that this may ultimately create an unsustainable situation, leading to the polarization of European society, while reinforcing inequality in access to healthcare.  Experts fear that in some countries only those who are wealthy enough to pay will be able to benefit from the latest – most advanced – treatments.

According to a 2015 industry report, the fear is that negative reimbursement recommendations for novel treatments in the United Kingdom and Ireland may also have economic consequences and make it more difficult for a number of pharmaceutical companies to justify their investments in these countries – in what they may view as an increasingly unattractive business environment. In turn, this could lead to the relocation research and development (R&D), as well as clinical trials programs, to other European countries.[6]

While the level of pharmaceutical prices does affect the pharmaceutical sector, which directly employs 633,100 people across Europe and spends in excess of €26 billion (US $ 30 billion) annually on R&D, slightly ahead of the United States, the expectation is that research in novel, innovative drugs, including antibody-drug conjugates and other targeted treatments, will only increase as a result of a better understanding of cancer biology and chemistry.[7]

Furthermore, while the expenditure of European member state on health care per capita varies greatly, these costs are closely correlated with GDP per capita. In turn, there is a positive relationship between health expenditure per capita and GDP per capita.

The higher-income states, including Austria, France, Germany, The Netherlands and Sweden spend, on average, more on health given their GDP per capita, allowing pioneering and innovative treatments – including targeted therapies and personalized medicine  – to be available for patients in these countries. [7]

In these countries, reimbursement programs reduce the financial burden of treatment, and thereby directly benefit patients.


Last Editorial Review: April 21, 2016

Featured Image: Researcher in Lab. Courtesy: © Fotolia Photo. Used with permission.

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

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Biparatopic HER2-targeting Antibody-drug Conjugate Demonstrates Potent Antitumor Activity

HER2-targeted therapies have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of breast cancer.  Being overexposed in 20-25% of human breast cancers and to a lesser degree in other cancer types, including gastric, lung and endometrial cancers, the HER2 protein is an important therapeutic target. HER2 expression levels vary across indication, but also across patients within an indication and within individual tumors.[1][2][3]

Independent from clinical features such as age, stage and tumor grade, HER2 expression is associated with a more aggressive tumor phenotype, worse prognosis and poor disease-free survival.  Furthermore, HER2 status has been shown to be predictive for response to certain chemotherapeutic agents such as doxorubicin (Adriamycin®/Rubex®) as well as HER2-targeted therapies like trastuzumab (Herceptin®; Genentech/Roche) an adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature) breast cancer, pertuzumab (Perjeta®; Genentech/Roche) a neoadjuvant and metastatic breast cancer treatment for patients with HER2-positive breast cancer, and lapatinib (Tykerb®; Novartis) a treatment indicated in combination with capecitabine for patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. [1]

Although proving effective in the treatment of HER2+ cancers, current HER2-targeted drugs are ineffective in killing cancer cells expressing relatively low levels of HER2. As a result, more than 60% of breast cancer patients are ineligible for HER2-targeted therapies because of lack of HER2 overexpression. Furthermore, a vast majority of eligible patients who initially respond to the treatment will eventually relapse. [2][3]

Researchers at MedImmune (Gaitersburgh, MD), the global biologics research and development arm of AstraZeneca are developing a novel HER2-targeting antibody-drug conjugate or ADCs to address this large, unmet, medical need.

During the San Antonio Breast Cancer Symposium (SABCS) being held in San Antonio, Texas, December 8 – 12, 2015, researchers presented results of a trial confirming that a bivalent biparatopic antibody targeting two distinct non-overlapping epitopes on HER2 is able to induce receptor clustering on the tumor cell surface.  This, in turn, this facilitates internalization and promotes lysosomal trafficking and degradation.

Photo 1.0: Attendees at registration center of the San Antonio Breast Cancer Symposium 2015.

Superior antitumor activity
When conjugated with a tubulysin-based microtubule inhibitor, the biparatopic antibody is able to deliver a greater quantity of cytotoxin into the targeted cancer cells.  As a result, it demonstrated superior antitumor activity over ado-trastuzumab emtansine (T-DM1, Kadcyla®; Genentech/Roche) in HER2-overexpressing (HER2-positive) tumor models.

This novel approach also induced complete tumor regression in a HER2-positive tumor model that had developed acquired resistance to ado-trastuzumab emtansine through chronic exposure.

Triple-negative breast cancer
In addition, to explore the potential clinical applications in treating the HER2 non-overexpressing (HER2-negative) patients, researchers evaluated the biparatopic antibody-drug conjugate across 17 primary tumor models derived from HER2-negative breast cancer patients. Among these models, 13 were derived from triple-negative breast cancer patients.

Triple negative breast cancer generally to occur more often in younger women and in women who are African-American or Hispanic/Latina. These cancers also tend to grow and spread more quickly than most other types of breast cancer. The aggressive behavior, poor outcome, and absence of targeted therapies makes the management of triple negative a challenge.

In addition to HER2, the researchers also considered other criteria in the selection of the 17 primary tumor models, including the degree of heterogeneity in HER2 expression, ER/PR status and histopathologic subclass, to maximize the diversity of tumor subtypes in the study.[4]

Biparatopic antibody-drug conjugate
Regardless of the histopathologic subclass and ER/PR status of the tumor, the biparatopic antibody-drug conjugates demonstrated potent anti tumor activity. At the dose of 1 mg/kg, 41% of the tumor models (7 out of 17) showed tumor regression and 6% (1 out of 17) showed tumor stasis. At the dose of 3 mg/kg, 71% of the models (12 out of 17) showed tumor regression and 12% (2 out of 17) showed tumor stasis.[4]

According to the researchers, these findings underscore the potential use of this novel HER2-targeting antibody-drug conjugate to treat a large patient population that is ineligible for or relapsed and/or refractory to current HER2-targeted therapies. They conclude that this result warrants futher investigation in the clinic.


Last Editorial Review: December 21, 2015

Photo and Featured image: The San Antonio Breast Cancer Symposium being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. 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: © MedMeetingImages/Todd Buchanan 2015. 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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Ado-trastuzumab Emtansine Fails Phase II/III GATSBY trial

Earlier today, in a short statement to the U.S. Securities Exchange Commission (SEC), ImmunoGen, Inc. disclosed that the Phase II/III Gatsby trial, a clinical trial designed to support a new indication for ado-trastuzumab emtansine (Kadcyla®; Roche/Genentech / also known as T-DM1) in second-line treatment of HER2-positive advanced gastric cancer being conducted by the drugs co-developer Roche, did not meet its primary endpoint.[1]

The filing did not provide any details on how the drug trial failed. Detailed clinical findings from the trial are expected to be released during a future medical conference.

Gatsby-trial
The Gatsby-trial is a multicenter, randomized study designed to evaluate the efficacy and safety of ado-trastuzumab emtansine compared to standard treatment with docetaxel or paclitaxel in patients with HER2-positive advanced gastric cancer.  A total of 412 patients already treated with first-line therapy participated in the study.[1]

The trial’s primary endpoint was overall survival (OS) over a time frame of approximately 3 years. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response, safety, response distribution of treatment-related symptoms, time to gastric cancer symptom progression, health related quality of life (hrQoL), and pharmacokinetics.

Image 1.0. The goal of treatment with an antibody-drug conjugate or ADC is to help address the challenge of balancing benefit vs. side effects by delivering  chemotherapy directly to cancer cells, limiting damage to healthy tissues. Click on image to enlarge.

According to the American cancer Society, gastric or stomach cancer is the second most common cause of cancer-related death in the world, leading to around 800,000 deaths each year, yet it is only the fourth most commonly diagnosed cancer, with around one million people diagnosed each year. [2] The incidence of this type of cancer varies geographically, with a higher prevalence in Asian countries (such as Korea) than in the West. Also, men are more prone to gastric cancer than women.

Approved indication
Ado-trastuzumab emtansine is currently approved by the U.S. Food and Drug Administration (FDA) for treatment of metastatic, HER2-positive breast cancer that has grown despite other HER2-targeting treatments. Researchers are investigating if the drug has potential in a number of other indications, including gastric and lung cancer.

Antibody-drug Conjugates or ADCs, including ado-trastuzumab emtansine, combine tumor-specific antibodies with powerful anticancer agents, providing potent cancer treatment while minimizing damage to healthy cells. ADCs are able to recognize and enter cancer cells and release cytotoxic agents once inside the cell, making this kind of drug less harmful to healthy, non-cancerous cells.

Earlier this year, ImmunoGen, Inc. entered into a royalty purchase agreement that monetized the Company’s royalties on sales of ado-trastuzumab emtansine. According to filed statements, the drug is expected to yield about $580.3 million in revenue this year.


Last editorial review: October 22, 2015

Photo: Roche Holding AG building. Image 1.0: Design of an ADC.  Photo/Image Courtesy: Roche Holding AG.

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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