The Antibody Society

the official website of the antibody society

An international non-profit supporting antibody-related research and development.

Antibody-drug conjugates in the spotlight

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square logo ADCAntibody-drug conjugates (ADCs) are designed to deliver cytotoxic agents into targeted cells, and they are typically developed as treatments for cancer. Due to the need for new cancer drugs, the development of ADCs is the focus of substantial efforts by the biopharmaceutical industry. Nearly 60 ADCs are currently in clinical studies, one ADC, inotuzumab ozogamicin, is undergoing regulatory review, and three ADCs have been granted approvals, although the first to be approved, gemtuzumab ozogamicin (Mylotarg®) was withdrawn from the market in 2010.

Two ADCs, brentuximab vedotin (Adcetris®) and ado-trastuzumab emtansine (Kadcyla®), are currently marketed in the United States (US) and European Union (EU), as well as other countries. These two ADCs are disparate in their composition, and are used as treatments for different indications. Brentuximab vedotin is composed of an anti-CD30 monoclonal antibody (mAb) conjugated to the tubulin inhibitor monomethyl auristatin E via a valine-citruline dipeptide linkage designed for conditional cleavage inside cells. In contrast, ado-trastuzimab emtansine comprises an anti-human epidermal growth factor receptor-2 (HER2) mAb coupled to the tubulin-disrupting maytansinoid DM1 drug via a non-reducible thioether linkage. Brentuximab vedotin was granted its first approval in 2011 for two indications: 1) classical Hodgkin lymphoma after failure of autologous hematopoietic stem cell transplantation or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates; and 2) systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. The first approval for ado-trastuzumab emtansine was granted in 2013; the product is indicated for the treatment of HER2-positive metastatic breast cancer in patients who previously received trastuzumab and a taxane separately or in combination.

Of the nearly 60 ADCs in the clinic, only two (depatuxizumab mafodotin, vadastuximab talirane) are currently in late-stage (Phase 2/3 or 3) clinical studies, but two additional ADCs (sacituzumab govitecan, mirvetuximab soravtansine) may transition to Phase 3 soon. Depatuxizumab mafodotin (ABT-414) is composed of an anti-epidermal growth factor receptor (EGFR) mAb conjugated to the tubulin inhibitor monomethyl auristatin F via a stable maleimidocaproyl linker. The Phase 2b/3 Intellance 1 study (NCT02573324) of the ADC with concurrent chemoradiation and adjuvant temozolomide in adult patients with newly diagnosed glioblastoma multiforme (GBM) with EGFR amplification was initiated in late 2015. Depatuxizumab mafodotin has orphan drug designations for GBM in the US and glioma in the EU, and it was granted a US Rare Pediatric Disease Designation for pediatric EGFR-amplified diffuse intrinsic pontine glioma, a brainstem tumor that is highly aggressive and difficult to treat. Vadastuximab talirane (SGN-33A) is an anti-CD33 mAb with 2 engineered cysteine residues through which DNA cross-linking pyrrolobenzodiazepine dimer drug moieties are conjugated via a protease-cleavable valine-alanine dipeptide linker. The Phase 3 CASCADE clinical trial (NCT02785900) of vadastuximab talirine in combination with azacitidine (Vidaza) or decitabine (Dacogen) in older patients with newly diagnosed acute myeloid leukemia (AML) was initiated in May 2016.  Results from a Phase 1 study indicated that the ADC in combination with hypomethylating agents was a well-tolerated regimen with a high remission rate in older patients with AML.

The transitions of sacituzumab govitecan (IMMU-132) and mirvetuximab soravtansine (IMGN853) to Phase 3 may occur by the end of 2016. The start of a Phase 3 study (NCT02574455) that will evaluate the safety and efficacy of sacituzumab govitecan in refractory/relapsed triple-negative breast cancer (TNBC) patients is scheduled for December 2016. This ADC has received US Breakthrough Therapy and Fast Track designations for the treatment of patients with TNBC. Sacituzumab govitecan comprises an anti-TROP-2 mAb conjugated via a pH-sensitive linker to SN-38, the active metabolite of the chemotherapeutic irinotecan, in a site-specific manner. Mirvetuximab soravtansine is being assessed as a single-agent therapy in the FORWARD I trial (NCT02631876) of the ADC versus investigator’s choice of chemotherapy in adults with folate receptor (FR)-α positive advanced epithelial ovarian cancer, primary peritoneal cancer or primary fallopian tube cancer, which is being changed from a Phase 2 to a Phase 3 trial. Mirvetuximab soravtansine is composed of an anti-FRα mAb linked to the tubulin-disrupting maytansinoid DM4 via a cleavable linker.

It should be noted that, despite the increased complexity of the molecules, ADCs are also the focus of companies developing biosimilar products. As discussed in previous Society posts, biosimilars of antibody-based drugs that have lost patent protection, including adalimumab (Humira®), rituximab (Rituxan®, Mabthera®), trastuzumab (Herceptin®) and etanercept (Enbrel®), are already approved or undergoing regulatory review in the US and EU, as well as other countries.

The Antibody Society thanks Hanson Wade for access to Beacon, the World ADC database.

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FDA approves Amjevita® (adalimumab-atto) as a biosimilar to Humira®

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Antibody impressionThe US Food and Drug Administration has approved Amjevita® (adalimumab-atto) as a biosimilar to Humira® (adalimumab). In adult patients, Amjevita® is approved for moderately to severely active rheumatoid arthritis; active psoriatic arthritis; active ankylosing spondylitis (an arthritis that affects the spine); moderately to severely active Crohn’s disease; moderately to severely active ulcerative colitis; and moderate to severe plaque psoriasis. Amjevita® is also indicated for moderately to severely active polyarticular juvenile idiopathic arthritis in patients four years of age and older.
Amjevita® is the third antibody-based drug to gain approval as a biosimilar in the US this year. Inflectra® (infliximab-dyyb), a biosimilar to Remicade® (infliximab), was approved in April 2016 and Erelzi® (etanercept-szzs) , a biosimilar to Enbrel® (etanercept), was approved in August 2016.

Antibody Engineering & Therapeutics

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Antibody Engineering & Therapeutics, the largest meeting devoted to antibody science and technology and the annual meeting of The Antibody Society, will be held in San Diego, CA on December 11-15, 2016. Each of 14 sessions will include presentations by leading industry and academic experts. In the meeting preview found here, the session chairs discuss the relevance of their topics to current and future antibody therapeutics development. Session topics include bispecifics and designer polyclonal antibodies; antibodies for neurodegenerative diseases; the interface between passive and active immunotherapy; antibodies for non-cancer indications; novel antibody display, selection and screening technologies; novel checkpoint modulators / immuno-oncology; engineering antibodies for T-cell therapy; novel engineering strategies to enhance antibody functions; and the biological impact of Fc receptor engagement. The meeting will open with keynote speakers Dennis R. Burton (The Scripps Research Institute), who will review progress toward a neutralizing antibody-based HIV vaccine; Olivera J. Finn, (University of Pittsburgh School of Medicine), who will discuss prophylactic cancer vaccines as a source of therapeutic antibodies; and Paul Richardson (Dana-Farber Cancer Institute), who will provide a clinical update on daratumumab for multiple myeloma. In a featured presentation, a representative of the World Health Organization’s INN expert group will provide a perspective on antibody naming. In addition, two pre-conference workshops covering ways to accelerate antibody drugs to the clinic and the applications of next-generation sequencing in antibody discovery and engineering will be held on Sunday December 11, 2016.

“Antibodies to watch in 2017” and progress on The Antibody Society’s 2016 initiatives will be presented during the Society’s special session on Wednesday, December 14, 2016. Janice Reichert, Executive Director of The Antibody Society, will recapitulate the approvals granted for antibody therapeutics in 2016 in the United States or European Union, and summarize the “Antibodies to watch” in 2017, i.e., monoclonal antibodies in regulatory review and those with Phase 3 clinical studies due for completion in 2017. She will also briefly discuss the Society’s initiative to address questions surrounding the World Health Organization’s international non-proprietary naming system.
Andrew Bradbury (Los Alamos National Laboratory), a member of the Society’s Board of Directors, will then review progress made during 2016 on the Society’s initiative to address issues related to antibody reagent reproducibility. In collaboration with the Global Biological Standards Institute, the Society organized the workshop “Research Antibodies: Solutions for Today and Tomorrow”, held at Asilomar in September 2016, with the goals to: 1) identify a set of standards to validate research antibodies, including recommendations for adoption by academia, industry, funders, and journals; 2) develop recommendations for an independent proficiency certification system or open access user ratings service; and 3) develop recommendations, timeline, and follow-up plan for the introduction of sequenced recombinant antibodies as research reagents. Dr. Bradbury will discuss the recommendations and conclusions that resulted from the Asilomar meeting and future plans for this initiative.
The Society supports the Adaptive Immune-Receptor Repertoire (AIRR) Community in developing recommendations for: 1) a common repository for AIRR sequence data, 2) minimal standards for publishing and depositing AIRR sequence data, and 3) resources and guidelines for the evaluation of molecular and statistical methods for AIRR sequence data, which were discussed at a workshop held at the National Institutes of Health’s Fishers Lane Facility in Rockville, MD in June 2016. Jamie K. Scott (Simon Fraser University),  a member of the Society’s Board of Directors, will provide an update on progress in these areas, and she will discuss future plans for this initiative.

Members of The Antibody Society receive a 15% discount on registration for this meeting! Contact us at membership@antibodysociety.org for the code. We look forward to seeing you in San Diego in December.

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Antibody-based biosimilar products approved in the EU or US

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Antibody impressionThe number of antibody-based biosimilar therapeutics approved in the European Union or United States is poised to grow substantially in 2016 and 2017. The originator products that target tumor necrosis factor (TNF) have been of particular interest to the biosimilar industry due to the expiration of key patents and the large global markets for the products. In 2013, the three top-selling originator anti-TNF products were infliximab (Remicade®), etanercept (Enbrel®) and adalimumab (Humira®), which combined had global sales of nearly $18 billion that year. The first biosimilar anti-TNF products approved in either the EU or US were Inflectra® and Remsima®, both of which are versions of infliximab.  Inflectra® and Remsima® were approved in the EU in September 2013 for rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis.

While no antibody-based biosimilar products were approved in either the EU or US in 2014 or 2015, two products have been approved in each of these regions so far in 2016, and more may be approved soon. In the EU, the biosimilar etanercept BENEPALI® was approved in January 2016 for moderate to severe rheumatoid arthritis, psoriatic arthritis, severe ankylosing spondylitis, severe non-radiographic axial spondyloarthritis, and plaque psoriasis, and the biosimilar infliximab Flixabi® was approved in May 2016 for rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis. In the US, Inflectra® was approved in April 2016 for the treatment of moderately to moderately to severely active rheumatoid arthritis, severely active Crohn’s disease, moderately to severely active ulcerative colitis, active ankylosing spondylitis, active psoriatic arthritis, chronic severe plaque psoriasis, and the biosimilar etanercept Erelzi® was approved in August 2016 for moderate to severe rheumatoid arthritis, moderate to severe polyarticular juvenile idiopathic arthritis, active psoriatic arthritis, active ankylosing spondylitis, and chronic moderate to severe plaque psoriasis. A biosimilar adalimumab (ABP-501) may be approved soon, as the Food and Drug Administration’s (FDA) Arthritis Advisory Committee voted unanimously to support approval of it in July 2016. The product was recommended for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis in patients aged 4 years and older, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, and plaque psoriasis.

Although the FDA does not release comprehensive lists of products in review, the European Medicines Agency (EMA) does provide limited information on applications for centralized marketing authorization under evaluation. As of August 3, 2016, a total of 6 applications for biosimilar adalimumab (3 applications), etanercept (1 application), and the anti-CD20 rituximab (2 applications) were under evaluation. In late August, EMA also accepted for review a marketing authorization application for a proposed biosimilar trastuzumab, which is used to treat certain HER2-positive breast and gastric cancers. Thus, there may soon be as many as 11 biosimilar antibody-based therapeutics on the market in the EU, and many of these could also gain approval in the US.

Antibodies to watch in 2016: Mid-year update

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mabs-coverSince 2010, the “Antibodies to watch” article series has documented annually the number and identities of commercially sponsored antibody therapeutics in Phase 3 studies, regulatory review and those recently approved in the US and EU. Taken together, the articles have captured the extraordinary doubling of the number of antibody therapeutics in Phase 3 studies from 26 to 53, as identified in the “Antibodies to watch in 2010” and “Antibodies to watch in 2016” articles, respectively. Due to the highly dynamic nature of antibody therapeutics development, numerous transitions have occurred during 2016, and the Society offers here a mid-year update to data reported in the “Antibodies to watch in 2016” article.

As described in our previous posts, 4 antibody therapeutics (atezolizumab, reslizumab, ixekizumab, obiltoxaximab) were granted first marketing authorizations in either the US or EU during January to June 2016. As of mid-2016, marketing applications for 8 antibody therapeutics are being considered for first approvals in the US or EU. Of these, 5 applications (olaratuzumab, bezlotoxumab, sarilumab, brodalumab, ocrelizumab) have Food and Drug Administration action dates during September -December 2016. Recommendations by the European Medicines Agency on applications for Xilonix and inotuzumab ozogamicin could be made in 2016, but additional time would be needed for the European Commission’s decision regarding whether to grant the marketing authorization. It thus remains to be seen whether the number of antibody therapeutics approved in the US or EU during 2016 will match or exceed the record of 9 approvals granted in a single year set in 2015.

As of mid-2016, 53 unique antibody therapeutics were in Phase 3 studies. This is the same total number noted in the “Antibodies to watch in 2016” article, but the antibodies included in the totals are not all the same. The tables included in this mid-year update result from the addition of antibodies that started a first Phase 3 study in late 2015 to mid-2016, and deletion of antibodies that transitioned to regulatory review, reverted to an earlier clinical phase or had their development suspended or terminated. Compared to the totals included in the “Antibodies to watch in 2016” article, the number of antibodies in Phase 3 studies for cancer indications as of mid-2016 decreased slightly (from 17 to 15, respectively), while those for non-cancer indications increased slightly (from 36 to 38, respectively).

Antibodies for cancer represent only 28% of the current commercial Phase 3 pipeline, although they are ~55% of the overall clinical pipeline of therapeutic antibodies. The 15 antibody therapeutics in Phase 3 studies for cancer indications are notable for the diversity in their composition. Of the 15, 6 (40%) are non-canonical antibodies (1 radiolabeled antibody, 1 scFv-containing liposome, 2 immunotoxins, 2 antibody-drug conjugates (ADCs)), and a majority of the canonical antibodies (i.e., full-length IgG1, 2 or 4) are Fc- or glyco-engineered to enhance functionality. The 2 ADCs now in Phase 3 studies represent a vanguard, as this type of antibody therapeutic has entered clinical studies in large numbers only recently. Of the ADCs currently in clinical studies, most (44/56, 79%) are in either Phase 1 or Phase 1/2 studies, and most (55/56) are for cancer indications. ADCs now comprise ~20% of the clinical pipeline of antibodies for cancer, but ~11% of all antibodies in clinical development. There is substantial diversity of the targets, drugs, linkers, and drug-to-antibody ratios of the ADCs in the clinic. For example, of the ADCs in the clinic, targets for 51 have been disclosed, and 39 of these 51 targets are unique, i.e., only one ADC in clinical studies is known to target that particular antigen. Antigens known to be the target of more than one ADC in clinical studies include CD19, CD37, EGFR, HER2 and mesothelin. The diversity of the molecules may initially serve as a hindrance, but knowledge gained by the development of this class of molecules should increase overall as more ADCs enter clinical studies, transition through the phases and join the two ADCs currently on the market, brentuximab vedotin (Adcetris®) and ado-trastuzumab vedotin (Kadcyla®).

Antibodies for non-cancer indications dominate the current commercial Phase 3 pipeline. Unlike the antibodies for cancer, the 38 antibodies in Phase 3 studies for non-cancer indications are mostly canonical full-length IgG1, 2 or 4 molecules. Only 4 of the 38 (~11%) are non-canonical molecules: 1 bispecific antibody and 3 antibody ‘fragments’ (scFv, Fab, nanobody). Like ADCs, bispecific antibodies are expected to comprise a larger percentage of the Phase 3 pipeline in the next ~6-8 years. Bispecific antibodies now comprise ~9% of the entire commercial pipeline of antibody therapeutics, but most (32/45, 71%) of those are currently in early clinical studies (either Phase 1 or Phase 1/2). Compared to ADCs, bispecific antibodies are undergoing evaluation in a broader range of indications, although the majority of bispecifics (30/45, 67%) are for cancer and they comprise ~11% of the clinical pipeline of antibodies for cancer. The two bispecific antibodies now on the market, catumaxomab (Removab®) and blinatumomab (BLINCYTO®), are both for cancer. Nevertheless, the one bispecific antibody now in Phase 3 studies, emicizumab, is for a non-cancer indication (hemophilia A).

The clinical pipeline of antibody therapeutics, including at Phase 3, is highly dynamic. The Antibody Society will continue to track antibodies in the clinic, and report progress to its members.

Acknowledgements: The Antibody Society thanks Hanson Wade for access to the Beacon ADC database.

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