9:50 Manipulating the Tumor Microenvironment to Enhance Effector Function for Improved Antibody Efficacy in Patients
Stephen Beers, Ph.D., Associate Professor, Antibody & Vaccine Group, University of Southampton
Successful antibody therapy appears to rely predominantly on Fcγ receptor expressing effector cells such as macrophages. Unfortunately, a number of cancers have proven resistant to antibody therapy potentially due to the adverse effects of the tumor microenvironment on these cells. Here, the potential of harnessing tumor associated macrophages as effectors will be discussed as well as means presented by which they may be re-programmed to enhance their antibody effector capacity.
10:20 Coffee Break
10:45 A Cell-Penetrating Antibody Technology Platform: Making the Undruggable Druggable
Hua Eleanor Yu, Ph.D., Billy and Audrey L. Wilder Endowed Professor of Tumor Immunology, Co-Leader of Cancer Immunotherapeutics Program, City of Hope Comprehensive Cancer Center
We have developed a novel technology platform to allow efficient cell-penetration of proteins/antibodies in vitro and in vivo. Using flow cytometry, confocal imaging and Western blotting, we demonstrate the self-penetrating ability of the modified antibodies. Both local and systemic administrations of the modified antibodies effectively inhibit their intracellular targets in tumors, resulting in tumor cell apoptosis and tumor regression in multiple models. Our discoveries enable the development of a new class of research tools and novel therapeutics.
11:15 The Effect of Molecular Weight, PK, and Valency on Tumor Biodistribution and Efficacy of Antibody-Based Drugs
Ruth Muchekehu, Ph.D. Research Scientist, Vertex Pharmaceuticals
To explore the role of pharmacokinetics, valency, and size on tumor targeting, the biodistribution of an FGFR4 targeting CovX-body (an FGFR4-binding peptide linked to a non-targeting IgG scaffold; 150 kDa), F(ab)2 (100 kDa) and Fab (50 kDa) fragments was measured. The highest percent of injected drug was achieved with the IgG, and increasing the valency of the IgG by conjugating a homodimeric peptide to the scaffold, translated into superior efficacy.
11:45 How to Leverage Oncogene Addiction: Targeted Biological Therapy Inducing Growth Factor Receptor Internalization and Degradation
John Haurum, M.D., D.Phil., CEO, F-star GmbH & F-star Biotechnology Ltd.
FS102 is a HER2-specific Fcab™ (Fc with antigen binding). In HER2-overexpressing tumour cells, FS102 induce profound HER2 degradation and apoptosis, and FS102 eliminates HER2-overexpressing tumours in patient-derived mouse xenograft models. We present this as an example of a general class of oncogene-targeted biological therapies, which induce tumour killing via internalization and degradation of the addictive growth factor receptor.
12:15 pm Enjoy Lunch on Your Own
2:00 Chairperson’s Remarks
John Haurum, M.D., D.Phil., CEO, F-star GmbH & F-star Biotechnology Ltd.
2:05 Targets for Antibodies in Neuro-Oncology: Getting Past the Blood-Brain Barrier
Lois Lampson, Ph.D., Associate Professor of Surgery, Brigham and Women’s Hospital
Antibody-mediated therapy for brain tumors is thought to face two hurdles: The blood-brain barrier (BBB) and, for some effector mechanisms, the presumed “immune privilege” of the brain. Here we ask, for different kinds of brain tumor targets: Are the BBB or “privilege” really the key problems? How different is the brain, really, from other sites?
2:35 Alternative Immune Models for Generating Novel Antibodies to Highly Conserved Oncology Targets
William “Jonny” Finlay, Ph.D., Director, Pfizer
Many novel oncology targets are highly conserved between humans and rodents, making it slow and laborious to generate high potency, highly specific antibodies that cross-react with multiple orthologs. Alternative immune models can therefore be a very valuable resource to rapidly generate exemplary antibodies against unique epitopes. These antibodies allow investigators to validate and de-risk novel targets and mechanisms of action, in a variety of in vivo models, at pace.
3:05 SAR650984, A CD38 Monoclonal Antibody for Selected CD38+ Hematological Malignancies
Francisco Adrian, Ph.D., Section Head, Sanofi Oncology
CD38 is a type II transmembrane glycoprotein highly expressed at the surface of malignant multiple myeloma plasma cells. SAR650984 is a humanized IgG1 antibody targeting CD38 in PhII clinical trials. The preclinical characterization of SAR650984 will be presented, including epitope mapping, impact on CD38 enzymatic activity, pro-apoptotic activity in MM cellular models and patient samples, and in vivo activity in combination with bortezomib.
3:35 Fluorescent Human Synthetic Nano-antibodies (snAbs) Highlight Specifically Cancer Cells to Guide Oncology Surgeons in Efficient Removal of Cancerous Tumors
Marek Malecki, M.D., Ph.D., CEO, Phoenix Biomolecular Engineering Foundation
The most difficult problem, for surgeons pursuing removal of cancerous tumors, is to determine the borders of the tumors, so that they can remove cancerous tissue, while minimizing iatrogenic injury to the healthy tissue. To resolve this problem, we designed and manufactured fluorescent, human, synthetic nano-antibodies (snAbs) against cancer cells. The cancer cells were specifically, strongly, and permanently highlighted with our fluorescent snAbs, while making them easy to distinguish from healthy cells in vivo.
3:50 Refreshment Break
4:15 A Novel T Cell Bispecific Antibody Targeting EGFRvIII to Specifically and Potently Kill Tumor Cells in vitro and in vivo
Eugene Zhukovsky, Ph.D., CSO, Research, Affimed Therapeutics AG
We developed tetravalent, bifunctional antibodies that recognize EGFRvIII, the deletion variant III of EGFR. The expression of EGFRvIII on various solid tumor types, and its absence from healthy tissues, provides an opportunity to develop cytotoxic antibodies that solely target cancer and spares normal tissues. Using a panel of biophysical and in vitro and in vivo functional assays we demonstrated that EGFRvIII/CD3 TandAbs are specific and highly potent drug candidates for the treatment of EGFRvIII+ malignancies.
4:45 Drugging the Undruggable: Using Knowledge-Based Design to Develop Antibodies against Difficult Targets
Gregory P. Adams, Ph.D., Co-Leader, Developmental Therapeutics Program, Fox Chase Cancer Center
The development of new clinically relevant antibodies has historically depended upon the immunization of animals or the selection of clones with desired specificity from large antibody libraries. While this works for many targets there are numerous important target epitopes that are difficult or even “undruggable”. Working with collaborators we have pursued a rational design approach employing structure prediction, loop grafting and computational combinatorial CDR display to develop antibodies specific for difficult targets.
5:15 Selection of Antibodies for T Cell Redirected Killing
Diego Ellerman, Senior Research Associate, Protein Chemistry, Genentech, Inc. – A Member of the Roche Group
T cell recruitment and redirected killing is a growing clinical strategy that is currently being explored for different oncological targets. This approach requires the use of bispecific antibodies targeting both the T cell receptor and a tumor-specific antigen. Different antibodies’ properties could play a role in determining the efficacy of the molecule, such as affinity, epitope location, binding geometry. We present case studies showing the influence of these factors.
Pharma Sources Insight January 2025
