title: A novel therapeutic strategy to rescue the immune effector function of proteolytically inactivated cancer therapeutic antibodies.
abstract: Primary and acquired resistance to anticancer antibody immunotherapies presents significant clinical challenges. Here, we demonstrate that proteolytic inactivation of cancer-targeting antibodies is an unappreciated contributor to cancer immune evasion, and the finding presents novel opportunities for therapeutic intervention. A single peptide bond cleavage in the IgG1 hinge impairs cancer cell killing due to structural derangement of the Fc region. Hinge-cleaved trastuzumab gradually accumulated on the surfaces of HER2-expressing cancer cell lines in vitro, and was greatly accelerated when the cells were engineered to express the potent bacterial IgG-degrading proteinase (IdeS). Similar to cancer-related matrix metalloproteinases (MMP), IdeS exposes a hinge neoepitope that we have developed an antibody, mAb2095-2, to specifically target the epitope. In in vitro studies, mAb2095-2 restored the lost antibody-dependent cell-mediated cytotoxicity functionality of cell-bound single-cleaved trastuzumab (scIgG-T). In vivo, mAb2095-2 rescued the impaired Fc-dependent tumor-suppressive activity of scIgG-T in a xenograft tumor model and restored the recruitment of immune effector cells into the tumor microenvironment. More importantly, an Fc-engineered proteinase-resistant version of mAb2095-2 rescued trastuzumab antitumor efficacy in a mouse tumor model with human cancer cells secreting IdeS, whereas trastuzumab alone showed significantly reduced antitumor activity in the same model. Consistently, an Fc-engineered proteinase-resistant version of trastuzumab also greatly improved antitumor efficacy in the xenograft tumor model. Taken together, these findings point to a novel cancer therapeutic strategy to rescue proteolytic damage of antibody effector function by an Fc-engineered mAb against the hinge neoepitope and to overcome cancer evasion of antibody immunity.
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, Houston, Texas.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Fan
authors.affiliation: Biologics Research, Janssen R&D, LLC, Spring House, Pennsylvania.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Brezski
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, Houston, Texas.
authors.forename: Hui
authors.initials: H
authors.lastname: Deng
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, Houston, Texas.
authors.forename: Pooja M
authors.initials: PM
authors.lastname: Dhupkar
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, Houston, Texas.
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Division of Oncology, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Anneliese
authors.initials: A
authors.lastname: Gonzalez
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Songlin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Biologics Research, Janssen R&D, LLC, Spring House, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Rycyzyn
authors.affiliation: Biologics Research, Janssen R&D, LLC, Spring House, Pennsylvania.
authors.forename: William R
authors.initials: WR
authors.lastname: Strohl
authors.affiliation: Biologics Research, Janssen R&D, LLC, Spring House, Pennsylvania.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Jordan
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, Houston, Texas. zhiqiang.an@uth.tmc.edu ningyan.zhang@uth.tmc.edu.
authors.forename: Ningyan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, Houston, Texas. zhiqiang.an@uth.tmc.edu ningyan.zhang@uth.tmc.edu.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: An
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D061986:MCF-7 Cells; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D059748:Proteolysis / Q000187:drug effects*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000068878:Trastuzumab / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D020782:Matrix Metalloproteinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab