Atezolizumab Approved Naked monospecific

Immune checkpoint target. Aglycosylated; Fc mutation (N297A) decreases effector function. MPDL3280A was isolated by screening a human phage display library (Genentech) against a recombinant extracellular domain (ECD)–Fc fusion of human PD-L1 (see US Patent US 8,217,149B2). A high-affinity antibody was selected from a single phage clone (YW243.55.S70) on a human IgG1 backbone. Affinity measurements were conducted by surface plasmon resonance (Biacore) and binding to PD-L1-expressing human T cells (Extended Data Fig. 10a). Binding of MPDL3280A was strictly dependent on the expression of human PD-L1, while other monoclonal antibodies (for example, trastuzumab) did not bind to the same cells. The selected antibody was also judged to compete with soluble PD-L1–ECD for binding to PD-1 and B7.1, either by blocking PD-L1–ECD-Fc binding to PD-1-or B7.1-expressing cells and PD-1–ECD or B7.1–ECD. The Fcdomainof MPDL3280A was engineered to render it effector-less by introducing an Asp to Ala change at position 298 in the CH2 domain of each heavy chain, which resulted in an anti-body devoid of N-linked oligosaccharides that was incapable of binding to human Fcc receptors (see US Patent US 8,214,149B2). In an in vitro assay for antibody-dependent cellular cytotoxicity (using human PBLs as effectors), the engineered anti-body was unable to mediate the killing of two cell lines transfected with human PD-L1, while efficient killing was observed using the unmodified ‘wild-type’ antibody. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. (2014) 515:563–7. doi: 10.1038/nature 14011