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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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Membership is free for students and employees of the Society’s corporate sponsors.

Novel engineering strategies to enhance antibody functions

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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! Here, Paul J. Carter, Ph.D., Senior Director and Staff Scientist, Antibody Engineering, Genentech, discusses what you will learn in his session on novel engineering strategies to enhance antibody functions, which will be held on Friday December 15, 2017.

A recurring theme with this conference since it began in the early 1990s has been the presentation of new antibody engineering technologies and their application to the design of antibodies for specific clinical applications. True to this tradition, this session will showcase a broad range of different antibody platform technologies for improving existing antibody properties or engineering antibodies with brand new capabilities. Antibody technologies to be highlighted include bispecific antibodies in many different formats, PEGylation, glyco-engineering and engineering of isoelectric point (pI).

Greg Lazar (Genentech) will present on agonizing the TNFR superfamily independent of FcgR-mediated cross-linking using multiple antibody technology platforms. This talk will highlight in vitro and in vivo proof-of-concept data. Taichi Kuramochi (Chugai Pharmabody Research) will provide a case study on pI engineering of an antibody variable domains and constant regions to enhance the potency of pH-dependent antigen binding antibody. Gestur Vidarsson (Sanquin Research) will describe how the natural glycans of antibodies can be tailored to increase ADCC and/or CDC activities. For example, combining hypergalactosylation with afucosylation increases the potency of ADCC activity beyond that achieved by afucosylation alone.

After the networking break, Martin Steegmaier (Roche Innovation Center Munich) will discuss applications of CrossMAbs in bivalent (1+1), trivalent (2+1) and tetravalent (2+2) formats for cancer immunotherapy and the use of novel targeting approaches for neurological diseases. Additionally, bispecific antibodies in DutaFab format for ophthalmologic diseases will be described.  Qing Li (Medimmune) will demonstrate tumor uptake of a PEGylated antibody fragment. Specifically, this presentation will focus on investigation of the correlation between hydrodynamic size, pharmacokinetic parameters and tumor uptake of a PEGylated diabody. Kartik Chandran (Albert Einstein College of Medicine) will close the session by presenting a bispecific antibody “Trojan horse” approach for broad protection against ebolaviruses. One arm of the bispecific antibody binds a conserved epitope on ebolavirus glycoprotein. After internalization of the virus/antibody complex into cells and trafficking to late endosomes, the second arm of the bispecific blocks infection by binding to the viral entry receptor, NPC1.

Interested in attending the meeting? Society members can save 15% on the registration fee! Contact us at membership@antibodysociety.org for the code.

Not a member? Please join!

Membership is free for students and employees of the Society’s corporate sponsors.

The Antibody Society joins FOCIS!

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We are pleased to announce that The Antibody Society is now a Member Society of the Federation of Clinical Immunology Societies (FOCIS), which exists to improve human health through immunology by fostering interdisciplinary approaches to both understand and treat immune-based diseases. By joining FOCIS as a Member Society, our network has expanded to include over 60,000 clinicians and basic researchers dedicated to a cross-disciplinary approach to immunologic disease.

Information about Member Society and Individual Membership benefits, education opportunities, FOCIS publications and the FOCIS Member Society Roster can be found here. We look forward to working with FOCIS to achieve the goals shared by our organizations.

IMMUNO-ONCOLOGY: CHECKPOINTS

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The Antibody Society invites you to attend its annual meeting, Antibody Engineering & Therapeutics, on December 11-15, 2017 at the Manchester Grand Hyatt, San Diego, CA! In this summary, chairperson James Larrick, M.D., Ph.D., Managing Director and Chief Medical Officer, Panorama Research Institute and Velocity Pharmaceutical Development, discusses what you will learn at his session on immune-oncology checkpoints, which will be held on Friday December 15.

The management of cancer has dramatically changed over the past decade with the introduction of novel immunotherapies, chief among them inhibitors of checkpoint receptors — molecules whose function is to restrain the host immune response.  Antibodies inhibiting CTLA4 and PD1-PD-L1 have shown remarkable clinical benefit.  The field is evolving rapidly, with many clinical trials testing novel checkpoint inhibitors (e.g., anti-LAG3, anti-TIM3), alone, in combination, or with other targeted therapies. A sampling of novel approaches will be covered in this symposium.

This Friday morning (December 15, 2017) session will be led off by Mickey Hu (Panorama Institute of Molecular Medicine) who has developed a series of novel immunomodulatory drugs that suppress PD-L1 expression in tumor cells and inhibit the PD-L1/PD-1 checkpoint, resulting in the recruitment of natural killer (NK) cells into the tumor microenvironment that leads to tumor suppression. Efforts to combine immunomodulatory drugs with checkpoint blockades to overcome difficult-to-treat cancers with tolerable side effects will be described.

Clinical lead candidate antibodies often lack species cross-reactivity, necessitating the development of substitute antibodies for pre-clinical development in mice or monkeys. Next, Erik Hofman, (Argenx) will describe the use of the SIMPLE Antibody platform to generate functional human-mouse cross-reactive antibodies against several validated immune checkpoint proteins, including PD-1, VISTA and LAG-3.

Xin Lu (University of Notre Dame) will present data indicating that targeted therapy against myeloid-derived suppressor cells, using multikinase inhibitors such as cabozantinib and dactolisib, can synergize with immune checkpoint blockade antibodies (e.g., anti-CTLA4, anti-PD1) to eradicate metastatic castration-resistant prostate cancer.

A key feature of effective cancer immunotherapy relies on enhanced anti-tumor immune response and reduced suppressive effects. As natural cytokines are made to maintain a balance between activation and suppression, they are often unable to achieve desired therapeutic efficacy. Cheng-I Wang (Biomedical Sciences Institutes, ASTAR, Singapore) will describe a cytokine receptor agonist antibody that mimics IL-2’s immune stimulatory effects on CD8 T cells with minimal Treg activation.

Cow antibodies have unusually long CDR3 regions. Vaughn Smider (The Scripps Research Institute) has characterized the genetic and structural properties of these antibodies, and has identified novel antibodies against HIV and exhausted T-cell targets utilizing this approach.

The final speaker, Sarah Crome, (Princess Margaret Cancer Centre, University Health Network, Canada) will describe efforts to characterize a unique innate lymphoid cell (ILC) population that suppresses the expansion and function of tumor-associated T cells, and is associated with early recurrence in high-grade cancer. This regulatory ILC population has properties that overlap with NK cells and other defined ILCs, yet can be differentiated by a distinct gene expression signature. Studies defining molecular interactions that control regulatory ILC function and ways to target this population to enhance immunotherapy will be presented.

Interested in attending the meeting? Society members can save 15% on the registration fee!

Not a member? Please join!

Membership is free for students and employees of the Society’s corporate sponsors.

Biological Impact of Fc Receptor Engagement

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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! In this summary, session organizers Trudi Veldman (Senior Director Biologics, AbbVie Bioresearch Center) and Chung-Ming Hsieh (Executive Director, Biologics Discovery Boston, Merck & Co.) discuss what you will learn at their session ‘Biological Impact of Fc Receptor Engagement’, which will be chaired by Chung-Ming Hsieh on Thursday December 14.

Antibodies are both binding proteins to their cognate targets and bridging molecules to downstream biological pathways via interaction with the various Fc receptors (e.g., FcγR and FcRn), complement, and lectins.  While our efforts in understanding the biology of therapeutic antibodies are often initially focused on the variable domain and target engagement, e.g., binding kinetics, potency, epitopes, it is crucial that we also gain understanding of the biology of the constant region of a therapeutic antibody and its impact on efficacy and safety.

This session aims to strengthen our current understandings on the biological impact of Fc receptor engagement.  The first presentation by Kenta Haraya (Chugai) will discuss the generation and characterization of a novel IgG1 Fc variant with optimized binding to FcRn that does not have increased binding by rheumatoid factors.  This Fc variant has been incorporated into a recycling antibody being developed for complement-mediated diseases.

The next three presentations will focus on the impact of FcγR engagement on antitumor activities of protein therapeutics.  Rony Dahan (Rockefeller) will present the finding that the antitumor activity of a human CD40 agonistic antibody is dependent on FcγRIIb engagement and is inhibited by FcγRIIa engagement, highlighting the importance of Fc domain optimization for improved efficacy.  Moving beyond antibodies, Daniel Christ (Garvan Institute of Medical Research) will present data indicating that the potent antitumor activity of interleukin-2-Fc fusion protein requires Fc-mediated depletion of regulatory T-cells.  Lastly, Frederick Arce Vargas (University College London Cancer Institute) will present the depletion of tumor-infiltrating regulatory T cells by an Fc-optimized anti-CD25 in synergy with PD-1 blockade to eradicate established tumors.

The field also continues to make progress in engineering Fc for modulating antibody effector functions, FcγR or complement engagement, and circulating half-life.  To this end, James Ernst (Genentech) will present effector function-attenuating mutations that maintain antibody stability and reduce toxicity.  George Georgiou (University of Texas at Austin) will present a set of novel engineered Fcs for half-life extension and for highly selective engagement of a single FcγR or C1q.

The full agenda for the meeting can be found here.

Interested in attending the meeting? Society members can save 15% on the registration fee!

Not a member? Please join!

Membership is free for students and employees of the Society’s corporate sponsors.