What is it about?

Porustobart (HBM4003, or the HCAb 4003-2 in the research paper) is a fully human heavy chain-only antibody to CTLA4. By enhanced ADCC Fc modification, it shows potent Treg depletion activity in in-vitro assays, in-vivo mouse model and ongoing human clinical trial. It is a potential next generation CTLA4 therapy comparing to ipilimumab which has much weaker Treg depletion and tricky adverse effect in patients.

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Why is it important?

It further supports that the CTLA4 therapy is at least partially relied on Treg depletion. The Treg depletion is not dependent on long exposure of anti-CTLA4 antibody in in-vivo based on the pharmacodynamic experiments. The design of porustobart molecule is to improve the efficacy by enhancing Treg killing and to reduce toxicity by shorter exposure. Preclinical studies show promising results although the human trial is most critical to corroborate this design.

Perspectives

After another decade of research on immuno-oncology in the field, very few IO targets are really validated in human trials besides PD1/L1, CTLA4, Lag3 ... However, even for these validated targets, we still have a lot to learn about their mode of actions. Continuous research and breakthrough on target biology will lead to new generation of therapies. Every small steps on science and technology drives better life for patients.

Yiping Rong

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This page is a summary of: An anti-CTLA-4 heavy chain–only antibody with enhanced T reg depletion shows excellent preclinical efficacy and safety profile, Proceedings of the National Academy of Sciences, August 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2200879119.
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