Utilizing PK and PD Biomarkers to Guide the First-in-Human Starting Dose Selection of MTBT1466A: A Novel Humanized Monoclonal Anti-TGFβ3 Antibody for the Treatment of Fibrotic Diseases.

Autor:	Yadav R; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, USA. Electronic address: yadavr13@gene.com., Sukumaran S; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, USA., Lutman J; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, USA., Mitra MS; Safety Assessment, Genentech Inc., South San Francisco, CA, USA., Halpern W; Safety Assessment, Genentech Inc., South San Francisco, CA, USA., Sun T; Immunology Discovery, Genentech Inc., South San Francisco, CA, USA., Setiadi AF; BioAnalytical Sciences, Genentech Inc., South San Francisco, CA, USA., Neighbors M; Translational Medicine, Genentech Inc., South San Francisco, CA, USA., Sheng XR; Translational Medicine, Genentech Inc., South San Francisco, CA, USA., Yip V; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, USA., Shen BQ; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, USA., Liu C; BioAnalytical Sciences, Genentech Inc., South San Francisco, CA, USA., Han L; Clinical Pharmacology, Genentech Inc., South San Francisco, CA, USA., Ovacik AM; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, USA., Wu Y; Antibody Engineering, Genentech Inc., South San Francisco, CA, USA., Glickstein S; Early Clinical Development, Genentech Inc, South San Francisco, CA, USA., Kunder R; Early Clinical Development, Genentech Inc, South San Francisco, CA, USA., Arron JR; Immunology Discovery, Genentech Inc., South San Francisco, CA, USA., Pan L; Clinical Pharmacology, Genentech Inc., South San Francisco, CA, USA., Kamath AV; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, USA., Stefanich EG; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, USA. Electronic address: erics@gene.com.
Jazyk:	angličtina
Zdroj:	Journal of pharmaceutical sciences [J Pharm Sci] 2023 Nov; Vol. 112 (11), pp. 2910-2920. Date of Electronic Publication: 2023 Jul 08.
DOI:	10.1016/j.xphs.2023.07.005
Abstrakt:	MTBT1466A is a high-affinity TGFβ3-specific humanized IgG1 monoclonal antibody with reduced Fc effector function, currently under investigation in clinical trials as a potential anti-fibrotic therapy. Here, we characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of MTBT1466A in mice and monkeys and predicted the PK/PD of MTBT1466A in humans to guide the selection of the first-in-human (FIH) starting dose. MTBT1466A demonstrated a typical IgG1-like biphasic PK profile in monkeys, and the predicted human clearance of 2.69 mL/day/kg and t 1/2 of 20.4 days are consistent with those expected for a human IgG1 antibody. In a mouse model of bleomycin-induced lung fibrosis, changes in expression of TGFβ3-related genes, serpine1, fibronectin-1, and collagen 1A1 were used as PD biomarkers to determine the minimum pharmacologically active dose of 1 mg/kg. Unlike in the fibrosis mouse model, evidence of target engagement in healthy monkeys was only observed at higher doses. Using a PKPD-guided approach, the recommended FIH dose of 50 mg, IV, provided exposures that were shown to be safe and well tolerated in healthy volunteers. MTBT1466A PK in healthy volunteers was predicted reasonably well using a PK model with allometric scaling of PK parameters from monkey data. Taken together, this work provides insights into the PK/PD behavior of MTBT1466A in preclinical species, and supports the translatability of the preclinical data into the clinic. Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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