1. Immunomodulation of T- and NK-cell Responses by a Bispecific Antibody Targeting CD28 Homolog and PD-L1.
- Author
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Ramaswamy M, Kim T, Jones DC, Ghadially H, Mahmoud TI, Garcia A, Browne G, Zenonos Z, Puplampu-Dove Y, Riggs JM, Bhat GK, Herbst R, Schofield DJ, and Carlesso G
- Subjects
- B7-H1 Antigen metabolism, CD28 Antigens metabolism, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Humans, Immunotherapy, Killer Cells, Natural, Lymphocyte Activation, Programmed Cell Death 1 Receptor metabolism, Antibodies, Bispecific metabolism, Neoplasms metabolism
- Abstract
Checkpoint blockade therapies targeting PD-1/PD-L1 and CTLA-4 are clinically successful but also evoke adverse events due to systemic T-cell activation. We engineered a bispecific, mAb targeting CD28 homolog (CD28H), a newly identified B7 family receptor that is constitutively expressed on T and natural killer (NK) cells, with a PD-L1 antibody to potentiate tumor-specific immune responses. The bispecific antibody led to T-cell costimulation, induced NK-cell cytotoxicity of PD-L1-expressing tumor cells, and activated tissue-resident memory CD8
+ T cells. Mechanistically, the CD28H agonistic arm of the bispecific antibody reduced PD-L1/PD-1-induced SHP2 phosphorylation while simultaneously augmenting T-cell receptor signaling by activating the MAPK and AKT pathways. This bispecific approach could be used to target multiple immune cells, including CD8+ T cells, tissue-resident memory T cells, and NK cells, in a tumor-specific manner that may lead to induction of durable, therapeutic antitumor responses., (©2021 American Association for Cancer Research.)- Published
- 2022
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