title: Identification and Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal Antibody.
abstract: Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR.
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom. StewartR@medimmune.com.
authors.forename: Ross
authors.initials: R
authors.lastname: Stewart
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Michelle
authors.initials: M
authors.lastname: Morrow
authors.affiliation: MedImmune LLC, Gaithersburg, Maryland.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Hammond
authors.affiliation: MedImmune LLC, Gaithersburg, Maryland.
authors.forename: Kathy
authors.initials: K
authors.lastname: Mulgrew
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Danielle
authors.initials: D
authors.lastname: Marcus
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Edmund
authors.initials: E
authors.lastname: Poon
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Amanda
authors.initials: A
authors.lastname: Watkins
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mullins
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Chodorge
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Andrews
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Bannister
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Dick
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Crawford
authors.affiliation: Abbvie Inc, Worcester, Massachusetts. Previously AstraZeneca Ltd.
authors.forename: Julie
authors.initials: J
authors.lastname: Parmentier
authors.affiliation: Acceleron Pharma, Inc, Cambridge, Massachusetts. Previously Astrazeneca Ltd.
authors.forename: Marat
authors.initials: M
authors.lastname: Alimzhanov
authors.affiliation: CDRD, University of British Columbia, Vancouver, British Columbia, Canada. Previously Amgen Inc.
authors.forename: John S
authors.initials: JS
authors.lastname: Babcook
authors.affiliation: Amgen Inc, Burnaby, British Columbia, Canada.
authors.forename: Ian N
authors.initials: IN
authors.lastname: Foltz
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Buchanan
authors.affiliation: AstraZeneca Ltd, Waltham, Massachusetts.
authors.forename: Vahe
authors.initials: V
authors.lastname: Bedian
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
authors.affiliation: Kymab Ltd, The Bennet Building, Babraham Research Campus, Cambridge, United Kingdom. Previously MedImmune Ltd.
authors.forename: Matthew
authors.initials: M
authors.lastname: McCourt
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000378:metabolism; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001667:Binding, Competitive; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; D009944:Organoplatinum Compounds; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077150:Oxaliplatin; C000613593:durvalumab