title: The Role of Anti-Drug Antibodies in the Pharmacokinetics, Disposition, Target Engagement, and Efficacy of a GITR Agonist Monoclonal Antibody in Mice.
abstract: Administration of biologics to enhance T-cell function is part of a rapidly growing field of cancer immunotherapy demonstrated by the unprecedented clinical success of several immunoregulatory receptor targeting antibodies. While these biologic agents confer significant anti-tumor activity through targeted immune response modulation, they can also elicit broad immune responses potentially including the production of anti-drug antibodies (ADAs). DTA-1, an agonist monoclonal antibody against GITR, is a highly effective anti-tumor treatment in preclinical models. We demonstrate that repeated dosing with murinized DTA-1 (mDTA-1) generates ADAs with corresponding reductions in drug exposure and engagement of GITR on circulating CD3(+) CD4(+) T cells, due to rapid hepatic drug uptake and catabolism. Mice implanted with tumors after induction of preexisting mDTA-1 ADA show no anti-tumor efficacy when given 3 mg/kg mDTA-1, an efficacious dose in naive mice. Nonetheless, increasing mDTA-1 treatment to 30 mg/kg in ADA-positive mice restores mDTA-1 exposure and GITR engagement on circulating CD3(+) CD4(+) T cells, thereby partially restoring anti-tumor efficacy. Formation of anti-mDTA-1 antibodies and changes in drug exposure and disposition does not occur in GITR(-/-) mice, consistent with a role for GITR agonism in humoral immunity. Finally, the administration of muDX400, a murinized monoclonal antibody against the checkpoint inhibitor PD-1, dosed alone or combined with mDTA-1 did not result in reduced muDX400 exposure, nor did it change the nature of the anti-mDTA-1 response. This indicates that anti-GITR immunogenicity may not necessarily impact the pharmacology of coadministered monoclonal antibodies, supporting combination immunomodulatory strategies.
authors.affiliation: Biologics DMPK and Disposition (N.D.B., D.W., D.H., E.E.), Immuno-oncology (S.M., D.G., R.U., A.M.B.), and Bioanalytics Department (S.Z.), Merck Research Laboratories, Merck & Co. Inc., Palo Alto, California.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Brunn
authors.affiliation: Biologics DMPK and Disposition (N.D.B., D.W., D.H., E.E.), Immuno-oncology (S.M., D.G., R.U., A.M.B.), and Bioanalytics Department (S.Z.), Merck Research Laboratories, Merck & Co. Inc., Palo Alto, California.
authors.forename: Smita
authors.initials: S
authors.lastname: Mauze
authors.affiliation: Biologics DMPK and Disposition (N.D.B., D.W., D.H., E.E.), Immuno-oncology (S.M., D.G., R.U., A.M.B.), and Bioanalytics Department (S.Z.), Merck Research Laboratories, Merck & Co. Inc., Palo Alto, California.
authors.forename: Danling
authors.initials: D
authors.lastname: Gu
authors.affiliation: Biologics DMPK and Disposition (N.D.B., D.W., D.H., E.E.), Immuno-oncology (S.M., D.G., R.U., A.M.B.), and Bioanalytics Department (S.Z.), Merck Research Laboratories, Merck & Co. Inc., Palo Alto, California.
authors.forename: Derek
authors.initials: D
authors.lastname: Wiswell
authors.affiliation: Biologics DMPK and Disposition (N.D.B., D.W., D.H., E.E.), Immuno-oncology (S.M., D.G., R.U., A.M.B.), and Bioanalytics Department (S.Z.), Merck Research Laboratories, Merck & Co. Inc., Palo Alto, California.
authors.forename: Roanna
authors.initials: R
authors.lastname: Ueda
authors.affiliation: Biologics DMPK and Disposition (N.D.B., D.W., D.H., E.E.), Immuno-oncology (S.M., D.G., R.U., A.M.B.), and Bioanalytics Department (S.Z.), Merck Research Laboratories, Merck & Co. Inc., Palo Alto, California.
authors.forename: Douglas
authors.initials: D
authors.lastname: Hodges
authors.affiliation: Biologics DMPK and Disposition (N.D.B., D.W., D.H., E.E.), Immuno-oncology (S.M., D.G., R.U., A.M.B.), and Bioanalytics Department (S.Z.), Merck Research Laboratories, Merck & Co. Inc., Palo Alto, California.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Beebe
authors.affiliation: Biologics DMPK and Disposition (N.D.B., D.W., D.H., E.E.), Immuno-oncology (S.M., D.G., R.U., A.M.B.), and Bioanalytics Department (S.Z.), Merck Research Laboratories, Merck & Co. Inc., Palo Alto, California.
authors.forename: Shuli
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Biologics DMPK and Disposition (N.D.B., D.W., D.H., E.E.), Immuno-oncology (S.M., D.G., R.U., A.M.B.), and Bioanalytics Department (S.Z.), Merck Research Laboratories, Merck & Co. Inc., Palo Alto, California Enrique.escandon@merck.com.
authors.forename: Enrique
authors.initials: E
authors.lastname: Escandón
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000819:agonists* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053450:Glucocorticoid-Induced TNFR-Related Protein; C106544:Tnfrsf18 protein, mouse