Alyssa Klee '18   

Title:​  The Identification of the Binding Sites of PD-1, B7-1, and Atezolizumab on PD-L1 as a Strategy to Reduce Toxicities of Novel Immunotherapies
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Problem:
Many antibodies in current immunotherapies block more than one inhibitory “pathway”. This results in the increased activation of T cells, and therefore increased side effects for the patient. Although this may occur in many common treatments, the identification of the unknown binding site between two proteins, PD-L1 and B7-1, would benefit the countless weaker patients who cannot handle these side effects.

Activities & Interests:
Founder and President of Somers Cancer Research, Founder and President of Math National Honor Society, SHS Varsity Volleyball, Downstate Juniors Volleyball, Chem Club President, National Honor Society, Spanish National Honor Society, Spanish Club, Leo's Club, Netflix, Puppies.

Abstract:
​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.