Klee, Alyssa - The Identification of the Binding Sites of PD-1, B7-1, and Atezolizumab on PD-L1 as a Strategy to Reduce Toxicities of Novel Immunother

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Immune checkpoint inhibitors such as Atezolizumab have had tremendous success; however, they cause increasingly toxic immune related adverse events (irAEs) depending on the inhibitor used. Pharma companies should recognize that a cause of Atezolizumab’s (TECENTRIQ) irAEs could be that it blocks the two overlapping binding sites of PD-1 and B7-1. Recent studies reveal a novel pathway between PD-L1 and B7-1, resulting in the inhibition of T cell proliferation and cytokine secretion. Blocking more than one pathway can activate significantly more T cells than expected. Although this benefits patients who tolerate the irAEs, many patients cannot. The solution is to create an antibody binding to PD-L1 in a non-overlapping region, where only PD-1 or B7-1 should bind. Previously, part of the binding site of B7-1 on PD-L1 was discovered, but not enough residues were known for a complete picture of the non-overlapping region for drug development. Recently, several amino acids were mutated, creating a more complete picture of the site of B7-1 on PD-L1. The FDA approved drug Atezolizumab was tested to determine which residues it binds to on PD-L1. With this information, new drugs can be produced blocking only one pathway instead of two, resulting in fewer immunotherapy side effects.

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