title: PD-L1 blockade for cancer treatment: MEDI4736.
abstract: MEDI4736 is a human immunoglobulin (Ig) G1к monoclonal antibody that blocks programmed cell death ligand-1 (PD-L1) binding to its receptors, allowing T cells to recognize and kill tumor cells. Key attributes include high affinity and selectivity for PD-L1, sustained drug exposure for up to 1 year of dosing, and engineering of the antibody to prevent antibody-dependent cell-mediated cytotoxicity. No immunogenicity impacting on the pharmacokinetics/pharmacodynamics of MEDI4736 has been reported at the 10 mg/kg every 2 weeks dose selected for further clinical development. The current safety profile and encouraging early anti-tumor activity of MEDI4736 support further clinical assessment. A broad development program for MEDI4736, both as monotherapy and in combination, is underway across a range of tumor types. This includes a large, multicenter, phase I, dose-escalation/expansion study in solid tumors (with a smaller corresponding study in Japanese patients), a phase I study in myelodysplastic syndrome, and a phase II study in advanced colorectal cancer. In addition, multiple phase I combination studies are ongoing with different agents, including those targeting MEK/BRAF in melanoma, epidermal growth factor receptor, programmed cell death-1, cytotoxic T-lymphocyte antigen-4, OX40, chemokine (C-C motif) receptor 4, and indoleamine 2,3-dioxygenase. Development is most advanced in non-small cell lung cancer, with a program currently comprising four pivotal studies and three phase I combination studies. A pivotal program for MEDI4736 in head and neck cancer began in late 2014.
authors.affiliation: AstraZeneca Immuno-Oncology, Gaithersburg, MD. Electronic address: Ramy.Ibrahim@astrazeneca.com.
authors.forename: Ramy
authors.initials: R
authors.lastname: Ibrahim
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Stewart
authors.affiliation: AstraZeneca Immuno-Oncology, Gaithersburg, MD.
authors.forename: Aiman
authors.initials: A
authors.lastname: Shalabi
mesh_terms: D000818:Animals; D006801:Humans; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000378:metabolism; D002986:Clinical Trials as Topic; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C000613593:durvalumab