AI Article Synopsis

  • Hu8F4 is a high-affinity T cell receptor-like antibody, which has been adapted into a chimeric antigen receptor (CAR) format to target a specific leukemia-associated antigen known as PR1/HLA-A2.
  • The modified Hu8F4-CAR(PQ) version includes changes to the Fc receptor binding sites to reduce adverse effects like activation-induced cell death and off-target killing by mouse immune cells.
  • Studies show that both adult and cord blood-derived Hu8F4-CAR(PQ)-T cells can effectively destroy leukemia cells in human and mouse models, demonstrating their potential for targeted cancer therapy.

Article Abstract

Hu8F4 is a T cell receptor (TCR)-like antibody with high affinity for leukemia-associated antigen PR1/HLA-A2 epitope. Adapted into a chimeric antigen receptor (CAR) format, Hu8F4-CAR is comprised of the Hu8F4 scFv, the human IgG1 CH2CH3 extracellular spacer domain, a human CD28 costimulatory domain, and the human CD3ζ signaling domain. We have demonstrated high efficacy of Hu8F4-CAR-T cells against PR1/HLA-A2-expressing cell lines and leukemic blasts from AML patients . Previous studies have shown that modification of the Fc domains of IgG4 CH2CH3 spacer regions can eliminate activation-induced cell death and off-target killing mediated by mouse Fc gamma receptor (FcgR)-expressing cells. We generated Hu8F4-CAR(PQ) with mutated Fc receptor binding sites on the CH2 domain of Hu8F4-CAR to prevent unwanted interactions with FcgR-expressing cells . The primary human T cells transduced with Hu8F4-CAR(PQ) can specifically lyse HLA-A2 PR1-expressing leukemia cell lines . Furthermore, both adult donor-derived and cord blood-derived Hu8F4-CAR(PQ)-T cells are active and can eliminate U937 leukemia cells in NSG mice. Herein, we demonstrate that modification of the IgG1-based spacer can eliminate Fc receptor-binding-induced adverse effects and Hu8F4-CAR(PQ)-T cells can kill leukemia .

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10925463PMC
http://dx.doi.org/10.21203/rs.3.rs-3937972/v1DOI Listing

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