High-affinity CD16-polymorphism and Fc-engineered antibodies enable activity of CD16-chimeric antigen receptor-modified T cells for cancer therapy

• DOI: 10.1038/s41416-018-0341-1
• Publication Date: 2018-11-09T14:25:30Z
• Authors: Felicitas Rataj; Severin J. Jacobi; Stefan Stoiber; Florian Asang; Justyna Ogonek; Nicholas Tokarew; Bruno L. Cadilha; Erwin van Puijenb...; Constanze Heise; Peter Duewell; Stefan Endres; Christian Klein; Sebastian Kobold
• Keywords: 0301 basic medicine; Polymorphism, Genetic; Receptors, Chimeric Antigen; T-Lymphocytes; Receptors, IgG; Antibody-Dependent Cell Cytotoxicity; Antibodies, Monoclonal; Lymphocyte Activation; Immunotherapy, Adoptive; Article; Immunoglobulin Fc Fragments; 3. Good health; ErbB Receptors; Killer Cells, Natural; Mice; 03 medical and health sciences; Cell Line, Tumor; Neoplasms; Animals; Humans; Immunotherapy; Rituximab; Cell Proliferation

CD16-chimeric antigen receptors (CAR) T cells recognise the Fc-portion of therapeutic antibodies, which can enable the selective targeting of different antigens. Limited evidence exists as to which CD16-CAR design and antibody partner might be most effective. We have hypothesised that the use of high-affinity CD16 variants, with increased Fc-terminus antibody affinity, combined with Fc-engineered antibodies, would provide superior CD16-CAR T cell efficacy.CD16-CAR T (wild-type or variants) cells were co-cultured with Panc-1 pancreatic cancer, Raji lymphoma or A375 melanoma cells in the presence or absence of anti-CD20, anti-MCSP, wild-type or the glycoengineered antibody variants. The endpoints were proliferation, activation, and cytotoxicity in vitro.The CD16 158 V variant of CD16-CAR T cells showed increased cytotoxic activity against all the tested cancer cells in the presence of the wild-type antibody directed against MCSP or CD20. Glycoengineered antibodies enhanced CD16-CAR T cell activity irrespective of CD16 polymorphisms as compared with the wild-type antibody. The combination of the glycoengineered antibodies with the CD16-CAR 158 V variant synergised as seen by the increase in all endpoints.These results indicate that CD16-CAR with the high-affinity CD16 variant 158 V, combined with Fc-engineered antibodies, have high anti-tumour efficacy.