CTLA-4 was commercially validated as the first target to correct immune defects in cancer patients through antibody-based immunotherapy. However, CTLA-4-targeting drugs currently in clinical use or testing cause immunotherapy-related adverse events (irAE) in high percentages of cancer patients. Drs. Liu and Zheng, our co-founders, demonstrated that the cancer immunotherapeutic effect (CITE) and irAE are mediated by distinct mechanisms and thus can be uncoupled through engineering of antibodies with stronger CITE but minimal irAE.
ONC-392, a humanized IgG1 monoclonal antibody, with modified Fc, is such an antibody that targets CTLA-4 in a unique way to selectively eliminate tumor-infiltrating regulatory T cells (Treg) without affecting T cell activation in the peripheral T cells. Compared with other commercial and clinical stage anti-CTLA-4 antibodies, ONC-392 has more robust CITE but dramatically lower irAE in preclinical models. A Phase 1A/1B clinical trial is currently underway to assess the safety, pharmacokinetics, and efficacy of ONC-392 as a single agent in advanced solid tumors and in combination with anti-PD(L)1 standard of care in Non- Small Cell Lung Cancer (NSCLC) (PRESERVE-001, NCT04140526).
Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy.
Zhang Y, Du X, Liu M, Tang F, Zhang P, Ai C, Fields JK, Sundberg EJ, Latinovic OS, Devenport M, Zheng P, Liu Y.
Cell Res. 2019 Aug;29(8):609-627. doi: 10.1038/s41422-019-0184-1.
How Does an Anti-CTLA-4 Antibody Promote Cancer Immunity?
Liu Y, Zheng P.
Trends Immunol. 2018 Dec;39(12):953-956. doi: 10.1016/j.it.2018.10.009.
Uncoupling Therapeutic from Immunotherapy-related Adverse Effects for Safer and Effective Anti-CTLA-4 Antibodies in CTLA4 Humanized Mice.
Du X, Liu M, Su J, Zhang P, Tang F, Ye P, Devenport M, Wang X, Zhang Y, Liu Y, Zheng P.
Cell Res. 2018 Apr;28(4):433-447. doi: 10.1038/s41422-018-0012-z.
A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy.
Du X, Tang F, Liu M, Su J, Zhang Y, Wu W, Devenport M, Lazarski CA, Zhang P, Wang X, Ye P, Wang C, Hwang E, Zhu T, Xu T, Zheng P, Liu Y.
Cell Res. 2018 Apr;28(4):416-432. doi: 10.1038/s41422-018-0011-0.
Human CTLA-4-knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-CTLA-4 antibodies.
Lute KD, May KF Jr, Lu P, Zhang H, Kocak E, Mosinger B, Wolford C, Phillips G, Caligiuri MA, Zheng P, Liu Y.
Blood. 2005 Nov 1;106(9):3127-33. doi: 10.1182/blood-2005-06-2298.