2016 Archived Content
Cambridge Healthtech Institute’s 8th Annual
Advancing Bispecifics and Combination Therapy to the Clinic
Including New Focus on Immunotherapy Targets
2 - 3 November 2016 | EPIC SANA Lisboa Hotel | Lisboa PORTUGAL
We live in exciting times for biotherapeutics as more and more products move into preclinical development and further into the clinic. There are many fascinating bispecific combinations and novel modes of action. This track on Advancing Bispecifics and Combination Therapy to the Clinic will present novel approaches for a range of therapeutic areas and will focus on preclinical and clinical challenges and how they are overcome.
Final Agenda
Day 1 | Day 2 | Speaker Biographies | Download Brochure
WEDNESDAY 2 NOVEMBER
07:45 Registration and Morning Coffee
08:30 Chairperson’s Remarks
Janine Schuurman, Ph.D., Vice President, Research, Genmab B.V.
08:35 KEYNOTE PRESENTATION:
Bispecific T Cell Engagers (BiTEs) for the Treatment of Malignant Diseases
Matthias Friedrich, Ph.D., Director, Nonclinical Development, Amgen Research (Munich) GmbH
09:20 Novel T Cell-Redirecting Bispecific Antibody Targeting a Highly Tumour Specific Antigen
Hirotake Shiraiwa, Ph.D., Group Manager, Biologics Discovery, Chugai Pharmaceutical Co., Ltd.
We have generated a T cell-redirecting antibody against a highly tumour specific antigen. This fully bispecific antibody recognises both CD3 and tumour-specific antigens and exerts highly potent anti-tumour efficacy in various in vivo models, and its
large scale production has been made possible by proprietary engineering technology. The findings observed in non-human primate toxicity studies were manageable and reversible. Optimisation, pharmacology, and toxicity of this antibody will be presented.
09:50 Development of REGN1979, a Fully Human CD20xCD3 Bispecific Antibody
Eric Smith, Ph.D., Associate Director, Bispecific Antibodies, Regeneron, Inc.
This presentation will describe the development of REGN1979, a fully human CD20xCD3 bispecific antibody generated with Regeneron’s VelocImmune® technology. Characterization of the in vitro and in vivo properties of this bispecific will be
discussed, along with findings from pre-clinical efficacy studies. In addition, an update on the clinical status of REGN1979 and future planned studies will be provided.
10:20 Delivery of CD20 (Rituxan)-Transferrin Receptor VNAR Bispecific Antibody to the Brain for Treatment of MS and Brain Cancer
Ktzysztof B. Wicher, Ph.D., Principal Scientist and Group Leader, Ossianix
Penetration of the BBB remains a significant impediment in the development of biologics for CNS-related diseases. We fused a transferrin receptor specific VNAR single domain antibody to Rituximab and found that such bispecifics shuttle to brain significantly
better with brain plasma ratios of between 2 to 5%. The hybrid proteins retain their binding to TfR1 and CD20 and mediate an ADCC response on human CD20+ cells. This offers a possible therapeutic approach for B cell mediated disease such as multiple
sclerosis and cerebral lymphoma.
10:50 Coffee Break in the Exhibit Hall with Poster Viewing
11:30 Development of a Highly Potent Anti-P-Cadherin / Anti-CD3 Bispecific DART Molecule with Extended Half-Life for the Treatment of Cancer
Adam Root, MSc, Senior Principal Scientist, Global BioTx Technologies, Pfizer, Inc.
We have made an extended-half-life dual-affinity re-targeting (DART) bispecific against P-cadherin and CD3 that demonstrates antibody-like properties. Identified through phage display and affinity-optimised to picomolar affinity, this bispecific molecule
elicits P-cadherin-expression level-dependent CTL responses against different tumour lines and induces antigen-dependent T cell activation and cytokine release. PF-06671008 demonstrates potent in vivo anti-tumour activity with significant tumour
growth inhibition observed across a range of tumour types expressing P-cadherin.
12:00 To the Clinic with T Cell-Engaging and Checkpoint-Inhibiting Bispecific Antibodies - A Modular Approach to Build and Develop Novel Cancer Immunotherapies
David E. Szymkowski, Ph.D., Senior Director, Research, Xencor, Inc.
Bispecific antibody-mediated co-engagement of T cells with tumour antigens is now a validated therapeutic strategy, but manufacturing and dosing concerns have slowed clinical development of such immunomodulatory drugs. We have engineered modular Fc-containing
bispecifics by coupling a robust and portable single-chain CD3 domain with full-length antibodies against promising cancer targets, and have also extended this Fc platform to generate multiple-checkpoint inhibiting bispecifics. I will present
case studies of several such bispecifics entering clinical development, supported by superior pharmacology and half-life in monkeys coupled with efficient commercial-scale manufacturing.
12:30 A Novel, Optimized Bispecific Antibody for the Treatment of PSMA-Expressing Cancer
Latifa Zekri, Ph.D., Cancer Immunology and Immunotherapy, German Cancer Consortium DKTK- DKFZ, Tuebingen
T cell recruiting bispecific antibodies (BsAbs) are promising reagents for tumor immunotherapy. However, BsAbs clinical development raised concerns about their low serum half-life, and toxicity due to off-target activation of T cells that prevents
the application of higher doses. To overcome these shortcomings we constructed a new PSMAxCD3 antibody, that exhibits reduced off-target T cell activation, increased serum half-life and potent tumor cell killing at limiting effector: target cell
ratios.
12:45 Characterization of a Cytomegalovirus-Specific BiTE
Charlotte Brey, MSc, Cellular Therapeutics, Children´s Cancer Research Institute, Vienna
Reactivation of human cytomegalovirus (HCMV) in immunocompromised patients after HSCT can still cause life-threatening complications. Therefore, we are investigating a Bispecific T cell engager (BiTE®) directed against the glycoprotein B (gB)
of HCMV, which is expressed on the surface of infected cells. The BiTE® was characterized for the first time, which comprised concentration allowing for efficient triggering of T cell effector functions such as degranulation, cytokine release
and cytotoxicity.
13:00 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
13:30 Session Break
14:00 Chairperson’s Remarks
Tariq Ghayur, Ph.D., Distinguished Research Fellow, Biologics, Abbvie Research
14:05 Design and Development of Next Generation Bispecific Antibodies for Cancer Immunotherapy
Jinming Gu, Ph.D., Executive Director, Biologics, Shanghai Hengrui Pharmaceuticals Co. Ltd.
Cancer immunotherapy has emerged as one of the major focuses in the pharmaceutical industry. The current limitation of anti-CTLA-4 or anti-PD-1 therapies is low response rate and high toxicity. This presentation will cover a few late stage preclinical
bispecific programs in cancer immunotherapy, e.g. CD40/X, OX-40/X, and CD3/X.
14:35 Finding the Right Balance: Selective and Safe Targeting of the Ubiquitous CD47 Checkpoint Receptor on Cancer Cells
Nicolas Fischer, Ph.D., Head, Research, NovImmune SA
The immune checkpoint CD47 represents an attractive target in oncology. However, due to the ubiquitous expressions of CD47, the use of monoclonal antibodies faces safety and pharmacology liabilities. We have developed NI-1701, a bispecific κλ
body, that selectively targets CD47 on B cells. CD47 inhibition drives effective phagocytosis of cancer cells in vitro and in vivo as well as the induction of durable anti-tumour responses in syngeneic animal models.
15:05 Vanucizumab, a Novel Bispecific Antibody Targeting VEGF-A and Angiopoetin-2: Preclinical and Clinical Development, and Preliminary Data on Combining with Cancer Immunotherapy
Oliver Krieter, M.D., Senior Translational Medicine Leader, Pharma Research and Early Development (pRED),
Roche
15:35 Refreshment Break in the Exhibit Hall with Poster Viewing
16:15 Duokines: A New Class of Bifunctional Immunostimulatory Molecule
Roland Kontermann, Ph.D., Professor, Biomedical Engineering, Cell Biology and Immunology, University
of Stuttgart
Duokines are bifunctional fusion proteins of TNF ligand superfamily members expressed either as homotrimer molecules or as single-chain derivatives. They act either in cis or in trans and are capable of amplifying immune responses, e.g. as shown for
the anti-tumour activity of T-cell retargeting bispecific antibodies.
16:45 Development of Bispecific DART Molecules to Mobilise Anti-Tumour Immunity
Ezio Bonvini, MD, SVP and CSO, Research, MacroGenics, Inc.
The DART® (Dual-Affinity ReTargeting) scaffold, a covalently-linked diabody-based bispecific module, can be tailored for single or multi-valency as well as fast or prolonged pharmacokinetics. Several DART molecules designed to recruit T cells
through co-engagement with cancer antigens are currently in clinical development. Furthermore, the DART platform is ideally suited for immunomodulation via co-checkpoint blockade, such as PD-1xLAG3. Preclinical studies supporting the development
of these DART molecules will be presented.
17:15 Problem-Solving Breakout Discussions
Table 1: Preclinical and Clinical Challenges for Bispecific Redirected T-Cell Killing
Moderator: Paul Moore, Ph.D., V.P. Cell Biology & Immunology, Macrogenics, Inc.
- Preclinical models and data
- Preclinical concerns, e.g. immunogenicity
- Safety/tox considerations
- Regulatory challenges
- Features of the clinical trial design
Table 2: Understanding the Pros and Cons of the Myriad Bi- and Multi-specific Antibody Formats
Moderator: David E. Szymkowski, Ph.D., Senior Director, Research, Xencor, Inc.
- Choosing your scaffold - implications for manufacturing, efficacy, and versatility
- How and why to manipulate valency and affinity for your therapeutic targets
- Effects of the format on delivery and dose
- CD3 bispecifics vs. other platforms - what's the next killer app?
- The future landscape: one size fits all, or bespoke tailoring?
Table 3: Manufacturing Considerations for Bispecifics
Moderator: Nicolas Fischer, Ph.D., Head, Research, NovImmune SA
- Fundamental differences for different formats
- Ensuring yield and purity
- Integrity and stability of the bispecific form
- Analytical and bioanalytical challenges
- Formulation challenges
18:15 Networking Reception in the Exhibit Hall with Poster Viewing
19:15 End of Day
Day 1 | Day 2 | Speaker Biographies | Download Brochure
THURSDAY 3 NOVEMBER
08:00 Registration and Morning Coffee
08:30 Chairperson’s Remarks
Nicolas Fischer, Ph.D., Head, Research, NovImmune SA
08:35 Functional Aspects of Antigen- and Fc-Dependent IgG Hexamer Formation
Janine Schuurman, Ph.D., Vice President, Research, Genmab B.V.
Monomeric antibodies of the IgG isotype can organise into ordered hexamers after binding their cognate antigen expressed on a cell surface. While unraveling the molecular mechanisms of IgG hexamerisation, we identified point mutations that either
inhibited or stimulated the formation of IgG hexamers and complement-mediated cytotoxicity (CDC). Our studies demonstrate that IgG hexamer formation, in addition to potentiating CDC, can induce outside-in signaling and activate intracellular signaling
pathways, which we will discuss using two Death Receptor 5 (DR5) specific antibodies.
09:05 Avidity Enhances the Efficacy of EGFR x cMet Bispecific Antibody
Mark Chiu, Ph.D., Associate Director, Structural Biology, Janssen Research and Development
Monovalent bispecific antibodies are typically thought to bind to their respective targets without avidity. However, we show how receptor densities of EGFR and cMet in different lung cancer cell lines can contribute to apparent synergy in targeting
both receptors. This impacts the use of an appropriate selection strategy of bispecific antibodies.
09:35 Antibody Mixtures: From Bench to Bedside
Michael Kragh, Ph.D., Senior Director, Preclinical Development, Symphogen
This presentation will outline the receptor internalisation and degradation with two antibodies targeting non-overlapping epitopes, and demonstrate the ability of antibody mixtures to eliminate resistance due to increased ligand production, ectodomain
escape mutations, or horizontal receptor cross-talk. It will also describe the MoA and translation into the clinic, and provide examples from development of two antibody mixtures, Sym004 (EGFR) and Pan-HER (EGFR, HER2, and HER3).
10:05 HERA - Hexavalent Receptor Agonists Targeting the TNFR-Superfamily for Cancer Immunotherapy
Oliver Hill, Ph.D., Vice President Molecular Biology, Apogenix AG
TNFRSF targeting compounds with a solely agonistic activity on immune cells are still rare. Apogenix's single-chain-based fusion proteins mimic the three-dimensional organization of the natural ligands (the TNFSF-proteins). In contrast to antibodies,
their agonistic activity does not rely on secondary crosslinking events in vitro nor in vivo. We will present the molecular engineering concept and the current results obtained for the TRAIL-R-, CD40-, GITR-, HVEM- and CD27-agonists.
10:35 Coffee Break in the Exhibit Hall with Poster Viewing
11:15 Clinical Developments with DVD Bispecifics
Tariq Ghayur, Ph.D., Distinguished Research Fellow, Biologics, AbbVie Research
This presentation will discuss: (i) Our efforts at building the DVD-Ig platform, including our preclinical and clinical experience to-date, (ii) our on-going efforts to identify novel target pairs, and (iii) our efforts in designing multi-specific
biologics to modulate immune responses.
11:45 Multifunctional DARPinTM Drugs – Next-Generation Oncology and Ophthalmology Treatment
Dan Snell, Ph.D., VP, Biology, Molecular Partners
The DARPinTM platform enables us to rapidly generate multi-functional drug candidates. Such drug candidates have the potential to improve therapy beyond current standard of care in ophthalmology and oncology. I will present interim data on the first-in-human
systemic clinical phase I of MP0250, a multi-domain oncology drug candidate targeting VEGF and HGF.
12:15 Enjoy Lunch on Your Own
13:00 Dessert Break in the Exhibit Hall with Poster Viewing
13:30 End of Advancing Bispecifics and Combination Therapy to the Clinic
Day 1 | Day 2 | Speaker Biographies | Download Brochure