MacroGenics, Inc. (NASDAQ:MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, today announced presentations at the American Association for Cancer Research (AACR) Virtual Annual Meeting II, taking place June 22-24, 2020.
“We are pleased to present data at this year’s AACR that highlight three platform technologies upon which multiple molecules are being developed at MacroGenics. We are presenting preclinical data for MGC018, our investigational antibody-drug conjugate targeting B7-H3, that provide evidence for an immune-mediated anti-tumor mechanism, as well as a rationale for clinical investigation of this molecule in combination with checkpoint blockade. Separately, we are presenting data from our novel Fc-engineered, bispecific DART® molecule that binds CD25 and CTLA-4 that is capable of depleting tumor-infiltrating regulatory T cells with high specificity in vitro,” said Ezio Bonvini, M.D., Senior Vice President and Chief Scientific Officer of MacroGenics. “Finally, one of the clinical investigators for flotetuzumab, our investigational CD123 x CD3 DART molecule, will be presenting preclinical data from his research with this molecule during an oral Education Session.”
AACR II Presentations
MGC018, a duocarmycin-based antibody-drug conjugate targeting B7-H3, exhibits immunomodulatory activity and enhanced antitumor activity in combination with checkpoint inhibitors
Poster Session: PO.ET07.01 - Cell Surface Antigens and Receptors as Drug Targets
MGC018 is an investigational antibody-drug conjugate targeting B7-H3 that has shown preliminary anti-tumor activity in an ongoing Phase 1 dose escalation study in patients with advanced solid tumors. The poster presented at AACR describes preclinical data suggesting that MGC018 can promote immune surveillance or stimulate immune responses to dying cancer cells that led to immunological memory, and when combined with checkpoint blockade may enhance anti-tumor activity.
These studies used a mouse model system designed to evaluate anti-tumor activity in an intact and functioning immune system. In this in vivo model, MGC018 demonstrated targeted activity against tumors expressing human B7-H3. Mechanistically, in vitro data suggested that MGC018 induced immunogenic cell death of target cells with the translocation of calreticulin to the cell surface during apoptosis. In addition, treatment with MGC018 in this model system led to an increased infiltration of T cells into the tumor microenvironment. Depleting these T cells attenuated the anti-tumor activity by MGC018, demonstrating their role in mediating response. Furthermore, MGC018 combined with an anti-PD-1 antibody enhanced anti-tumor activity observed in this study. Finally, mice that had achieved a complete response to initial treatment with MGC018 with or without checkpoint blockade survived longer when re-challenged with tumor without subsequent treatment compared to mice that had not received treatment with MGC018, suggesting immunological memory.
Investigational CD25 x CTLA-4 bispecific DART® molecule for depletion of tumor infiltrating Tregs via an enhanced Fc-dependent effector mechanism
Poster Session: PO.IM02.23 - Therapeutic Antibodies 1
The poster presented at AACR described a preclinical bispecific CD25 x CTLA-4 DART molecule containing an Fc region engineered to enhance clearance of target cells by antibody-dependent cellular cytotoxicity. This molecule was designed to deplete tumor-associated regulatory T cells co-expressing CD25 and CTLA-4 to reduce immune suppression mediated by these cells but preserve effector T cell function. CD25 is the alpha subunit of IL-2 receptor and CTLA-4 is a molecule involved in regulatory T cell function.
In vitro studies showed that the Fc-engineered bispecific CD25 x CTLA-4 DART molecule depleted regulatory T cells, with minimal effect on effector T cells. This depletion of regulatory T cells was shown to occur through an Fc-dependent mechanism, as a control CD25 x CTLA-4 DART molecule with an inactivated Fc domain had no effect in this assay. In addition, the bispecific CD25 x CTLA-4 DART molecule preserved cytotoxic T cell effector function in vitro compared to a combination of Fc-engineered monoclonal antibodies independently targeting CD25 and CTLA-4.
Immune escape after bone marrow transplantation: Hiding in plain sight
Educational Session: ED52 - Immunotherapy, Immune Evasion in Myeloid Malignancies, and Therapeutic Implications
John F. DiPersio, M.D., Ph.D., from Washington University School of Medicine in St. Louis, will present an overview of his research related to immune evasion and mechanisms of relapse after allogeneic hematopoietic cell transplantation (allo-HCT). The presentation will include preclinical data on flotetuzumab (MGD006), an investigational CD123 x CD3 bispecific DART molecule, suggesting a potential role for this molecule in treating patients with acute myeloid leukemia whose disease is relapsing after allo-HCT.
Date: June 24, 2020
Time: 5:30 - 5:50pm ET
Location: AACR Virtual Annual Meeting II at www.aacr.org
The posters will be available on the Events & Presentations page on MacroGenics’ website at http://ir.macrogenics.com/events.cfm.