Main Conference Day 3 - PT (Pacific Time, GMT-08:00)
Antibody engineering provides powerful strategies to address unmet medical needs, exemplified by the development of next generation T cell engagers (TCEs). We describe engineering and biological principles underlying CD8 guided TCEs designed to enhance therapeutic index and reduce the risk of cytokine driven toxicities. By preferentially engaging cytotoxic CD8⁺ T cells while limiting CD4⁺ T cell activation, this approach aims to minimize excessive cytokine production without compromising antitumor activity. Our AZD9793, GPC3 targeted, CD8 guided TCE induces potent hepatocellular carcinoma (HCC) cell killing with markedly reduced CD4⁺ T cell activation. This CD8 bias significantly limits the production of CRS related cytokines compared with a conventional GPC3×CD3 TCE, which activates CD8⁺ and CD4⁺ T cells equivalently.
- Xiuling Li - Director, AstraZeneca
Native immune responses are polyclonal in nature, yet most therapeutic antibodies to date are monoclonal. One limiting factor for the development of therapeutic polyclonal antibodies is the “chain-association issue” (incorrect chain pairing during co-expression of multiple antibodies). Here, we describe the generation of mutual exclusive CH3 interfaces to ensure correct H:H chain pairing. In combination with strategies addressing correct H:L chain pairing, this enabled the production of polyclonal antibody mixtures.
- Aran Labrijn, PhD - Director, Antibody Research and Technologies, Genmab
- Megan Rice - Associate Principal Scientist, AstraZeneca
This presentation will highlight the development of DLL3-targeted antibody-based radiotheranostic agents, spanning immunoPET imaging and targeted radioligand therapy. Preclinical and early clinical studies demonstrate the potential of DLL3 as a platform for patient selection, treatment monitoring, and precision radionuclide therapy across neuroendocrine malignancies.
- Salomon Tendler, MD, PhD - Assistant Attending Physician, Memorial Sloan Kettering Cancer Center