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Antibodies new to the market, and exiting

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On February 23, 2018, Kyowa Hakko Kirin Co. Ltd and its partner Ultragenyx Pharmaceutical Inc. announced that a conditional marketing authorization had been granted in the European Union (EU) for burosumab (Crysvita) as a treatment for X-linked hypophosphatemia in children 1 year of age and older, and adolescents with growing skeletons. Burosumab is a human IgG1 monoclonal antibody that binds to and inhibits the activity of fibroblast growth factor 23, thereby reducing loss of phosphate from the kidney and other metabolic abnormalities, and ameliorating bone changes that are a hallmark of the disease. The marketing approval in the EU is the first for burosumab. A biologics license application is undergoing review by the US Food and Drug Administration (FDA), and an action on the application is expected by April 17, 2018.

On February 27, 2018, Roche announced that emicizumab (Hemlibra®) had been approved in the EU for routine prophylaxis of bleeding episodes in people with hemophilia A with factor VIII inhibitors. Emicizumab, a bispecific IgG4 mAb targeting Factors IXa and X that originated at Chugai Pharmaceutical Co. Ltd., was approved by the FDA on November 16, 2017.

On March 2, 2018, Biogen and AbbVie announced the voluntary worldwide withdrawal of marketing authorizations for ZINBRYTA® (daclizumab) for relapsing multiple sclerosis (MS). The withdrawal coincides with an urgent review by the European Medicines Agency (EMA) of inflammatory brain disorder in 8 patients, and follows a 2017 review by EMA of reports of liver injury. Due to the risk of serious liver damage, EMA limited use of Zinbryta to MS patients who had tried at least two other disease modifying treatments and could not be treated with any other such treatments. ZINBRYTA® had been marketed in the EU, US, Switzerland, Canada and Australia.

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Emicizumab granted FDA approval

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Emicizumab (Hemlibra, emicizumab-kxwh, ACE910, RO5534262), a bispecific IgG4 mAb targeting Factors IXa and X, was approved by the FDA on November 16, 2017. The drug, which is administered once a week, was approved to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed Factor VIII inhibitors. The biologics license application was granted Priority Review and a Breakthrough Therapy designation. Hemlibra was also granted an orphan drug designation by the FDA.

Marketing applications for emicizumab are under review in the European Union and Japan; the European Medicines Agency is reviewing the marketing authorization application under accelerated assessment. Emicizumab was granted an orphan drug designation in Japan for the prevention and reduction of bleeding episodes in patients with congenital factor VIII deficiency with inhibitors. The drug was created by Chugai Pharmaceutical Co., Ltd. and co-developed by Chugai, Roche and Genentech.

The marketing applications for emicizumab include results from the Phase 3 HAVEN 1 (NCT02622321) study and interim analysis of the HAVEN 2 (NCT02795767) study. In the HAVEN 1 study, adult and adolescent patients (12 or older) who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point of the study was the difference in bleeding rates between Group A and Group B. Emicizumab was administered subcutaneously at a dose of 3 milligrams per kilogram per week (mg/kg/week) for 4 weeks followed by 1.5 mg/kg/week up to the end of the study. The annualized bleeding rate in Group A was reduced by 87% compared to Group B (2.9 events vs 23.3 events, P<0.001). [1] The HAVEN 2 study is evaluating the efficacy, safety, and pharmacokinetics of subcutaneous administration of emicizumab in hemophilia A pediatric patients with inhibitors.

1. Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, Santagostino E, Kruse-Jarres R, Negrier C, Kessler C, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9):809-818. doi: 10.1056/NEJMoa1703068.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of November 16, 2017, a total of 10 mAbs have been granted first approvals in either the US or EU in 2017, and marketing applications for a total of 9 antibody therapeutics that have not yet been approved in either the EU or US are undergoing review in these regions.

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Antibody-based innovations in the tumor microenvironment

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Please join us at the Society’s annual meeting, Antibody Engineering & Therapeutics on December 11-15, 2017 at the Manchester Grand Hyatt, San Diego, CA!

Clinical successes of the checkpoint modulators have revived the ambition to cure cancer by manipulation of the tumor microenvironment, or by unleashing or even priming (novel) adaptive immune responses. Hence, understanding the tumor microenvironment is an increasingly vital theme in the field of antibody-based therapeutics. This theme is excitingly addressed during two sessions “Antibody-based innovations in the tumor microenvironment 1 & 2”, jointly chaired by Kerry Chester and Janine Schuurman, which will be held on Thursday December 14, 2017. The sessions’ antibody-focused complementary topics are intended to expand knowledge at the cutting edge of the tumor microenvironment field, and are anticipated to boost lively discussions and stimulate new lines of thinking.

Antibody-based innovations in the tumor microenvironment (I, morning session)

Chairwomen: Kerry Chester, Professor of Molecular Medicine, UCL Cancer Institute, University College London, United Kingdom, and Janine Schuurman, Vice President Research, Genmab, Utrecht, The Netherlands

The sessions will open with a presentation by John Anderson (UCL) who will examine current thinking on immune evasion as a hallmark of cancer and why the solid tumor microenvironment is particularly hostile to immunotherapeutic function of effector cells. He will explain that, unlike adult cancers, pediatric cancers generally arise with few mutations and tend to be insensitive to existing immune modulators. Treatment approaches designed to target cell surface antigens in combination with agents to reverse immune evasion are likely to be required for this special group of patients.  New data will be presented in support of this hypothesis.

Syd Johnson (MacroGenics) will then share data on how to achieve co-stimulation of immune cells specifically within the tumor microenvironment using bispecific Dual-Affinity Re-Targeting (DART) and TRIDENT antibodies that bind both tumor-specific antigens and T-cell costimulatory molecules. Importantly, tumor binding is required to trigger costimulation. The talk will be illustrated with a case study showing how to achieve optimal tumor dependent T cell engagement by varying the relative position and valence of each antibody binding site in the molecule; manufacturability, stability and PK will also be addressed.

Natalia Arenas Ramirez (University Hospital Zurich) will then present an elegant antibody-based solution to problems associated with IL-2 immunotherapy.  IL2 binding to the IL-2 receptor α (CD25) subunit leads to unwanted side effects, including stimulation of immunosuppressive Tregs.  The talk will describe development of NARA1, an anti-IL-2 monoclonal antibody that acts as a high-affinity CD25 mimic, preferentially stimulating CD8+ cells while keeping the Tregs low.  Potent antitumor responses are achieved.

After the Networking Break, Volker Schellenberger (Amunix) will present an interesting approach to achieving activation in the tumor environment using bispecific T-cell engagers based on the ProTIA (Protease Triggered Immune Activator) platform. ProTIA combines tumor binding, proteolytic activation and polymer targeting due to an attached XTEN. Amunix’ lead molecule, AMX-168, is expected to enter clinical development in 2018.

Next, Shautong Song (Icell Kealex Therapeutics) will showcase an innovative way to focus treatment within the tumor microenvironment via bi-specific T-cell engager-armed oncolytic vaccinia virus. The treatment has several modes of action: vaccinia virus can directly lyse tumor cells and bi-specific T-cell engagement directs T-cells to kill both tumor and by-stander cells. In addition, T-cell engagement promotes T-cell infiltration into tumors and the cytokines released upon activation create a pro-inflammatory microenvironment that inhibits tumor growth. The strategy provides a sophisticated means of reducing systemic side effects associated with bi-specific T-cell engagers.

To complete the morning session, Dane Wittrup (Massachusetts Institute of Technology) will explore how classical monoclonal anti-tumor antibodies, such as anti-HER2 or anti-CD20, synergize with immune oncology antibodies, such as anti-PD-1. This is achieved not only by delivery of  tumor debris to antigen presenting cells for cross presentation, but also by creating a more inflammatory state and a localized cytokine storm in the tumor microenvironment.

Antibody-based innovations in the tumor microenvironment (II, afternoon session)

Chairwomen: Janine Schuurman, Vice President Research, Genmab, Utrecht, The Netherlands and Kerry Chester, Professor of Molecular Medicine, UCL Cancer Institute, University College London, United Kingdom

The afternoon session opens with a presentation centering on adaptive immune responses boosted by therapeutic cancer vaccines using RNA. Sebastian Kreiter (BioNTech) will focus on preclinical and clinical efforts to use personalized neoepitope vaccines in combination with immunomodulatory antibodies.

Edward Roberts (UCSF) will follow with a complementary line of thinking harnessing long term anti-tumor therapeutic effects. He will share data, including imaging data, to give us insights in the requirements for effective tumor antigen trafficking to the lymph nodes by the dendritic cells. These understandings may stimulate ideas for effective T cell priming approaches.

The TNFR super family (TNFR-SF) is a highly represented target class in the immunomodulatory targets space. Clustering is an important prerequisite for agonistic effects of antibodies against these targets. Nick Wilson (Agenus) will share emerging data on the role of antibody Fc and Fc-receptor biology to optimize the agonistic properties of antibodies against this target class.

Daratumumab, an anti-CD38 antibody that is approved for the treatment of relapsed / refractory myeloma, has multiple mechanisms of actions. Apart from rapid tumor cell reduction and direct anti-tumor effects, daratumumab significantly reduces CD38+ immune suppressive cells in the tumor microenvironment. Kate Sasser (Genmab) will focus on the immune modulatory activity of this antibody substantiated with data from in vitro evaluations and clinical studies.

Bispecific antibodies directed against both CD3and a tumor target can engage non-tumor-specific T cells, resulting in effective tumor-specific cell killing. Dirk Hose (Heidelberg University) will share data on a bispecific IgG-based molecule that targets CD3 and the B-cell maturation antigen (BCMA), which has been implicated in multiple myeloma. This presentation will cover the generation of this molecule and include early stage clinical learnings.

Anti-CD3 bispecifics can have severe toxicity profiles related to the expression profile of the tumor antigen. The last speaker of this full-day session on the tumor microenvironment will share data on the improvement of the therapeutic index of an anti-CD3 bispecific antibody also directed against a widely expressed antigen, epidermal growth factor receptor (EGFR). In this case study, Leila Boustany, (CytomX) will present the localization of the activity to the tumor microenvironment, which is accomplished by an engineering approach, i.e., a protease activatable EGFRxCD3 bispecific exploiting the protease activity present in the tumor microenvironment.

We anticipate that these complementary scientific insights focusing around antibody-based innovations in the tumor microenvironment will excite us all and inspire our forward-looking capabilities.

Interested in attending the meeting? Learn more from this PDF, which includes all session summaries written by the chairpersons.

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Bispecifics: shaking up the antibody product landscape

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Post written by Maarten Janmaat & Janine Schuurman

The antibody product landscape is continuously changing : more potent formats including antibody-drug conjugates and bispecific antibodies are on the rise (1). Although the concept of bispecifics has been known for more than 30 years, many technical challenges have only been resolved in recent years, resulting in bispecifics in different flavors entering the clinic. Numerous platforms, each with their own specific functional characteristics and manufacturing requirements, have led to two approved bispecific antibody products, catumaxomab and blinatumomab, and >50 bispecific antibody products in clinical evaluations (Figure 1). Roughly, the landscape of bispecific antibody platforms can be divided over 3 major classes: fragments, symmetric and asymmetric antibodies. Products representative of all 3 classes have reached the stage of clinical evaluation (Figure 2).

Multi-targeting approaches, including bispecifics, are generally being recognized to address disease heterogeneity and therapy escape. We believe, however, that the real excitement in the field of bispecific antibodies comes from the ability to couple two (or more) specificities, thereby introducing novel functionalities that were not present in the parent molecules. This class is also termed “obligatory bispecifics” by Spiess et al (2) and Labrijn et al (3).

Well-known examples of obligatory bispecifics, and the most validated use, are CD3 bispecifics, which activate T cells solely when bound in close proximity to a target-expressing cell, resulting in specific and effective tumor-cell killing. The two clinical approved therapeutics, catumaxomab and blinatumomab, belong to this class.

Another example of an innovative bispecific application is emicizumab (Chugai), which crosslinks Factor IXa and Factor X and mimics the natural function of Factor VIIIa. This Factor VIII replacement therapy is currently in a Phase 3 clinical trial in hemophilia patients (NCT02622321).

Bispecifics can also be used to guide translocation to immune-privileged sites, such as the human brain.  Yu et al have described a molecule that binds with one arm to the transferrin receptor, which guides crossing over the endothelium (4). Upon accessing the brain, the molecule binds to its therapeutic target β-secretase (BACE1), resulting in reduction of brain amyloid-β.

Recently, Wec et al. presented a very elegant ’Trojan horse’ bispecific approach to target Ebola infections (5). By combining knowledge of the molecular mechanisms of filovirus infection and the availability of mAbs against relevant epitopes, a molecule was generated that binds to a conserved surface-exposed Ebola epitope with one domain, while the second binding domains attacks the receptor  binding site within the endosomal compartment upon internalization, thereby preventing viral entry.

Some other interesting uses of obligatory bispecifics include enhanced lysosomal delivery of antibody-drug conjugates by targeting lysosomal membrane protein CD63 in combination with a tumor-specific target (6), fixing HER2 receptors in a conformational state (7) and induction of tumor cell DR5 clustering by using simultaneously binding to fibroblasts (8).

Taken together, technical progresses in the past years has advanced the development of therapeutic bispecific into the clinic.  In particular, obligatory bispecifics offer exciting and innovative treatment opportunities by revealing completely new functionalities.

What ideas do you have?

References
1.            J. Schuurman, P. W. Parren, Curr Opin Immunol 40, vii (Jun, 2016).
2.            C. Spiess, Q. Zhai, P. J. Carter, Mol Immunol 67, 95 (Oct, 2015).
3.            A. Labrijn, P. W. Parren, Science in press,  (2016).
4.            Y. J. Yu et al., Sci Transl Med 3, 84ra44 (May 25, 2011).
5.            A. Z. Wec et al., Science,  (Sep 8, 2016).
6.            B. E. de Goeij et al., Mol Cancer Ther,  (Aug 24, 2016).
7.            C. Jost et al., Structure 21, 1979 (Nov 5, 2013).
8.            P. Brunker et al., Mol Cancer Ther 15, 946 (May, 2016).

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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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