Using libraries of both engineered antibody domains (eAds) based on the IgG heavy chain variable domain (eVHd) and antibody fragments (Fabs), the University of Pittsburgh researchers developed panels of fully human single-domain eVHds and Fabs specific to CD276.
Description
CD276 (B7-H3) is a member of the B7 family of molecules involved in immune inhibition of T cell function and proliferation. Higher levels of CD276 expression are correlated with the development of cancer metastasis and cancer-specific mortality. CD276 is over-expressed on many solid tumor types, including prostate cancer, melanoma, squamous cell cancer of the head and neck, non-small cell lung cancer, and brain tumors; it is also found to be over-expressed in the tumor microenvironment, including on cancer stem-like cells and tumor vasculature and stroma, contributing to tumor angiogenesis and metastasis. Conversely, CD276 has restricted expression on non-cancerous tissue, making it a compelling target for anticancer therapy.
Applications
Immunotherapy for various solid tumors
Advantages
• This therapy is broadly applicable to the many solid cancers in which CD276 is over-expressed
• Expression of CD276 on both the tumor and tumor microenvironment creates the possibility of multiple additive anti-tumor benefits
• Preliminary experiments indicate antibodies target domains that may also serve as potent immune checkpoint blockades
• Much smaller size increases tumor penetration efficiency
• These antibodies have specific epitopes, especially the ones binding to membrane-proximal domain C2 can improve their efficacy
• These antibody domains and fragments to CD276 are of full human origin, suggesting less immunogenicity when used in humans
Invention Readiness
• In vivo data. The VH and Fab binders exhibited binding to recombinant CD276 protein on a nano-molar scale and the ability to specifically target cancer cell lines that over-express CD276.
IP Status
https://patents.google.com/patent/WO2023150092A2
https://patents.google.com/patent/US20240415884A1Related Publication(s)
Liu, X., Zhelev, D., Adams, C., Chen, C., Mellors, J. W., & Dimitrov, D. S. (2021). Effective killing of cells expressing CD276 (B7-H3) by a bispecific T cell engager based on a new fully human antibody. Translational Oncology, 14(12), 101232. https://doi.org/10.1016/j.tranon.2021.101232
Majzner, R. G., Theruvath, J. L., Nellan, A., Heitzeneder, S., Cui, Y., Mount, C. W., Rietberg, S. P., Linde, M. H., Xu, P., Rota, C., Sotillo, E., Labanieh, L., Lee, D. W., Orentas, R. J., Dimitrov, D. S., Zhu, Z., Croix, B. S., Delaidelli, A., Sekunova, A., … Mackall, C. L. (2019). CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors. Clinical Cancer Research, 25(8), 2560–2574. https://doi.org/10.1158/1078-0432.ccr-18-0432
