In the past year, advances in genome editing with CRISPR and immunotherapy have accelerated the pace of discovery of novel constructs to win the war against cancer. The armamentarium of tools has resulted in rapid progress in the advancement of new therapies
to the clinic, but a major bottleneck remains the discovery and validation of novel targets. The Novel Targets for Cancer and Emerging Therapeutic Areas conference at PEGS Europe will look at innovative approaches to uncover and vet novel targets
that can lead to first-in-class medicines in oncology and beyond.
Final Agenda
Scientific Advisory Board
Daniel Chen, MD, PhD, Chief Medical Officer, IGM Biosciences
Kerry Chester, PhD, Professor, Molecular Medicine, University College London Cancer Institute
Daniel Emerling, PhD, Senior Vice President, Research, Atreca, Inc.
Pablo Umaña, PhD, Head, Cancer Immunotherapy Discovery, Roche Innovation Center Zurich (Roche Glycart AG)
THURSDAY 21 NOVEMBER
13:00 Registration (Foyer A)
13:15 Dessert Break in the Exhibit Hall with Poster Viewing (Rio Pavilion)
14:00 Chairpersons’ Opening Remarks
Daniel Chen, MD, PhD, Chief Medical Officer, IGM Biosciences
Pablo Umaña, PhD, Head, Cancer Immunotherapy Discovery, Roche Innovation Center Zurich (Roche Glycart AG)
14:05 A New Era in Cancer Therapeutics: Biologic Problems and Engineering Solutions
Daniel Chen, MD, PhD, Chief Medical Officer, IGM Biosciences
The opportunity for therapeutics that turn on or off a singular target has largely been explored. However, advancements in our understanding of cancer, immune biology, and protein/cellular engineering approaches begin to define what seemed like science
fiction only a few years ago. The objectives and challenges for next-generation therapy and spatial temporal coordination of modulating different biologies and cell types within emerging cancer immunotherapy will be explored.
14:35 Novel Antibody Engineering to Improve Therapeutic Index of Antibody Targeting Solid Tumors
Kanako Tatsumi, PhD, Researcher, Discovery Biologics, Chugai Pharmaceutical Co. Ltd.
One of the remaining issues of antibody therapeutics is on-target off-tumor toxicity induced by binding to target antigens expressed in normal tissues. To overcome this issue, we have established a novel antibody engineering technology to enable antibody
to bind the antigen selectively at tumor site, but not at normal tissues.
15:05 OmniChicken
facilitated discovery of high affinity antibodies against the myeloid
checkpoint receptor SIRPa
Janet Sim, PhD, Vice President, Protein Science, ALX Oncology
Targeting the CD47/SIRPα pathway is an exciting new approach that shows promise in the clinic. As SIRPa expression is more restricted, it may offer differential safety and efficacy profile than CD47-targeted therapies. In this study, OmniChicken
was used to identify a panel of high affinity monoclonal antibodies that are cross-reactive to human, monkey and rodent SIRPα. Importantly, these antibodies bind to all human SIRPα variants, a critical attribute for global patient population.
Selected anti-SIRPa antibodies enhance the antitumor activity of checkpoint inhibitors and have favorable safety profiles. Altogether, these data support development of anti-SIRPa therapy, and provide opportunities to study similarities and differences
for targeting CD47 and SIRPa.
15:35 Networking Refreshment Break (Foyer D)
16:00 Avidity-Based Binding to HER2 Results in Selective Killing of HER2 Over-Expressing Cells by Anti-HER2/CD3
Teemu Junttila,
PhD, Senior Scientist, Translational Oncology, Genentech, Inc.
A primary barrier to the success of T cell-recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs.
To overcome this, we developed an anti-HER2/CD3 T cell-dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues.
Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase
the therapeutic index.
16:30 Tumor-Targeted 4-1BB Co-Stimulation to Boost T Cell Activity for Cancer Immunotherapy
Claudia Ferrara Koller, PhD, Group Leader, Roche Innovation Center Zurich
Endogenous costimulatory molecules on T cells, such as 4-1BB (CD137), can be leveraged for cancer immunotherapy. To overcome issues of first generation 4-1BB agonistic antibodies, we engineered proteins simultaneously targeting 4-1BB and a tumor-stroma
or tumor antigen (TA): FAP-4-1BBL (RG7826) and CD19-4-1BBL. In the presence of a T cell receptor (TCR) signal (endogenous or provided by a T cell bispecific antibody), they provide potent T cell costimulation strictly dependent on tumor target-mediated
hyper-clustering without systemic activation by FcgR-binding.
17:00 End of Day
17:00 Dinner Short Course Registration*
17:30 – 20:30 Dinner Short Courses
Recommended Short Course*
SC9: T Cell Therapies: Current Field, Challenges and Future Directions - LEARN MORE
*Separate registration required.
FRIDAY 22 NOVEMBER
08:00 Registration (Foyer A) and Morning Coffee (Foyer D)
08:30 Chairperson’s Remarks
Daniel Chen, MD, PhD, Chief Medical Officer, IGM Biosciences
08:35 Agonist and Bispecific IgM: Nature’s Approach to Highly Avid, Multivalent Antibodies
Bruce Keyt, PhD, CSO, IGM
Biosciences
Death receptor 5 (DR5) is widely expressed on tumor cells and directly induces apoptosis. Agonistic IgG anti-DR5 has preclinical efficacy, but not clinical efficacy. Multivalent IgM anti-DR5 induces receptor clustering and rapid tumor cell apoptosis.
In vitro, anti-DR5 IgM was 1,000-fold more potent compared to anti-DR5 IgG. In vivo, anti-DR5 IgM eradicated colorectal tumors and extended survival with leukemic models. We are
developing IgM anti-DR5 for treatment of solid and hematologic tumors.
09:05 Insights into the Mechanism of Action of ImmTAC® Molecules in Melanoma Patients
Marco Lepore, PhD,
Group Leader, Immunocore LLC
Immune mobilising monoclonal TCRs Against Cancer (ImmTAC) molecules are soluble bispecific T cell engagers which use high affinity TCRs fused to an anti-CD3 scFv to redirect polyclonal T cells toward tumor cells. ImmTAC molecules target tumour antigen-derived
peptides naturally presented by HLA molecules on the surface of cancer cells and induce multiple cytolytic and pro-inflammatory T cell responses. Here we will discuss key immunological aspects of ImmTAC mechanism of action and therapeutic activity
in advanced melanoma patients.
09:35 Bintrafusp Alfa (M7824): A New Class of Next Generation Immune-Oncology Agent Targeting PDL-1 and TGF-Beta
Michael R. Streit, PhD, Executive Director, Cancer Epigenetics, GlaxoSmithKline
10:05 Networking Coffee Break (Foyer D)
10:30 Chairperson’s Remarks
Kerry Chester, PhD, Professor, Molecular Medicine, University College London Cancer Institute
10:35 Rare Arginase 2 Specific Inhibitory Antibodies Restore T Cell Proliferation in vitro and Have a Novel Allosteric Mechanism of Inhibition
Maria Groves, PhD, Associate Director, R&D Antibody Discovery and Protein Engineering, AstraZeneca; Head, Cancer Research UK AstraZeneca Alliance Laboratory
Dysregulated expression of Arginase 2 (ARG2) within tumours has recently been proposed to result in significant levels of ARG2 in the extracellular matrix, generating an immunosuppressive niche that deactivates the immune system. Here we report the
identification, characterisation and affinity maturation of rare antibodies, typified by CMAL1158, which completely inhibit ARG2 activity but not ARG1 and restore T-cell proliferation in vitro. We have solved the crystal structure of
CMAL1158 and its parent, CMAL0187. CMAL1158 contacts a region of ARG2 away from the enzyme active site and induces major conformational changes in several regions of ARG2, which lead to subtle but important conformational changes at the active
site. A comparison with the parent CMAL0187:ARG2 crystal structure reveals that CMAL1158 has a significant epitope shift and a modified ‘angle’ of binding that creates a better enzyme inhibition profile. Inhibiting extracellular ARG2
with CMAL1158 could represent an exciting new strategy for stimulating the hosts immune system to fight tumours that release this immunosuppressive enzyme.
11:05 What Intratumoral Tregs Eat Makes Them Strong, but Vulnerable: A New Metabolic Intervention for Cancer Immunotherapy
Ping-Chih Ho, PhD, Assistant Professor, Oncology, University of Lausanne
Targeting intratumoral Tregs is a desirable strategy to reprogram the tumor microenvironment for cancer immunotherapy. However, the systemic impairment and destruction of Tregs caused by current strategies limit its application in cancer treatment.
Here, I will discuss how intratumoral Tregs support their survival and suppressive functions in the tumor microenvironment via metabolic adaptation and how targeting this metabolic machinery can lead to selective destruction of intratumoral Tregs.
11:35 Tertiary Lymphoid Structures and Tumor-Specific B Cell Response in Gastrointestinal Cancer
Hans Schlößer, MD, Principal Investigator, Cologne Translational Immunology, Center for Molecular Medicine Cologne
Tumor-infiltrating lymphocytes (TILs) are correlated to prognosis of several kinds of cancer. Most studies focused on T cells, while the role of tumor-associated B cells (TABs) has only recently gained more attention. TABs are highly differentiated
and frequently organize in tertiary lymphoid structures. Tumor-specific B cell response as well as composition and spatial distribution of TABs in gastrointestinal cancer will be discussed in the context of emerging immunotherapies.
12:05 Problem-Solving Breakout Discussions with a Light Snack
TABLE 28: Agonist Antibody Approaches
Moderator: Bruce Keyt, PhD, CSO, Research & Development, IGM Biosciences
- TNFrSF targeted therapies
- Multivalent constructs for active oligomerization
- Alternative strategies for trimerization
13:00 Chairperson’s Remarks
Daniel Emerling, PhD, Senior Vice President, Research, Atreca, Inc.
13:05 Using Phage Display of Antibodies as a Discovery Tool to Identify Disease-Related Targets
Peter
Kristensen, PhD, Head of Section of Biotechnology, Associate Professor, Department of Chemistry and Bioscience, Aalborg University
Large repertoires of recombinant antibodies displayed on filamentous bacteriophage can be applied as a discovery tool to identify new disease-related targets. As selection of recombinant antibodies can be performed on single cells in heterogeneous
population or tissue sections, the ability to identify posttranslational modified targets, or targets where localization is changed, is improved. Here a few examples will be given as to how recombinant antibody technology is used as a discovery
tool in cancer.
13:35 Microsphere Affinity Proteomics: High Throughput Deconvolution of Antibody Libraries
Fridtjof Lund-Johansen, MD, PhD, Senior Scientist, Department of Immunology, Oslo University Hospital, Norway
Microsphere Affinity Proteomics (MAP) is a versatile platform to study antibody-antigen interactions by flow cytometry. MAP antibody arrays provide means to probe 4,300 antibodies for binding of proteins from complex samples, such as cell and
tissue lysates, while MAP arrays with 12,000 full-length human proteins open new possibilities for assessing antibody specificity and detection of autoantibody targets.
14:05 Targeting Disease-Specific Inflammatory Stimuli: Novel Immunotherapies to Prevent or Reinforce Autoimmunity
Kim Midwood, PhD,
Professor, Kennedy Institute of Rheumatology, University of Oxford
Whilst immune defense against cancer is a key determinant of tumor elimination, mistargeted inflammation directed against healthy tissue underpins autoimmune disease pathogenesis. Investigating how regulatory control over endogenous triggers of
inflammation goes awry in rheumatoid arthritis, and how tumors exploit these mechanisms to evade immune surveillance, has led to the development of new therapies designed to prevent autoimmune joint destruction in arthritis and to re-educate
anti-tumoral immunity.
14:35 Functional Anti-Tumor Antibodies from Cancer Patients
Daniel Emerling, PhD, Senior Vice President, Research, Atreca, Inc.
By analyzing monoclonal antibodies derived from plasmablast IgG sequences of non-progressing cancer patients, we have identified more than 1,400 antibodies that bind to non-autologous human tumor tissue. These data, along with binding data from
both human and mouse tumor cell lines, suggest that these antibodies target public tumor antigens. Among these antibodies, we have antibodies that show anti-tumor functional activity in vitro and that show
activity in mouse tumor models. Our research on mechanism of action reveals potential for novel immuno-oncology targets and treatments.
15:05 End of Novel Targets for Cancer and Emerging Therapeutic Areas