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About The Speaker

Mitchell Ho

Senior Investigator and Deputy Chief of the Laboratory of Molecular Biology and Director of the Antibody Engineering Program at the Center for Cancer Research, NCI

Mitchell Ho

Dr. Mitchell Ho is a Senior Investigator and Deputy Chief of the Laboratory of Molecular Biology and Director of the Antibody Engineering Program at the Center for Cancer Research, NCI. Dr. Ho’s research encompasses investigating molecular mechanisms by which glypicans such as GPC1, GPC2 and GPC3 regulate Wnt signaling, as well as developing glypicans as cancer therapeutic targets.

His laboratory has constructed shark and camel single-domain antibody phage libraries to advance drug discovery. CAR-T cells developed in his laboratory are progressing towards clinical trials for the treatment of liver cancer, pediatric cancer and other malignancies. He is a fellow of the American Institute for Medical and Biological Engineering (AIMBE) and the founding Editor-in-Chief of Antibody Therapeutics (Oxford University Press). Dr. Ho received his Ph.D. from the University of Illinois at Urbana-Champaign.

Engineering Immunotoxins and CAR-T Cells for Cancer Therapy Using Nanobodies

We have studied cell surface glypicans as new cancer therapeutic targets and generated nanobody engineering-based immunotherapies. To develop GPC3 as a liver cancer target, we’ve generated HN3, which is a human single-domain antibody obtained through phage display technology.

The HN3-derived immunotoxin operates through a dual mechanism of action, deactivating cancer signaling pathways (Wnt and Yap) through the antibody domain and inhibiting protein synthesis via the toxin component. GPC1 and B7-H3 (CD276) are overexpressed in various cancer types. Utilizing our D4 nanobody against GPC1, we constructed CAR-T cells and found that a structurally rigid IgG4H and CD28TM domain brought the two nanobodies into close proximity, promoting CAR dimerization, enhancing T-cell signaling, and leading to tumor regression. B7-H3 has two distinct epitope motifs, IgC and IgV.

We’ve generated dromedary camel nanobodies targeting B7-H3 and have shown that CAR-T cells, based on nanobodies recognizing the IgC domain, exhibit potent anti-tumor activity against large tumors in mouse models. Our findings emphasize the critical role of the specific target antigen epitope in governing optimal CAR-T activity and offer nanobody-based therapeutics for use in cancer therapy.

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