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

Rajbharan Yadav; Siddharth Sukumaran; Jeff Lutman; Mayur S Mitra; Wendy Halpern; Tianhe Sun; A Francesca Setiadi; Margaret Neighbors; X Rebecca Sheng; Victor Yip; Ben-Quan Shen; Chang Liu; Lyrialle Han; Ayse Meric Ovacik; Yan Wu; Sara Glickstein; Rebecca Kunder; Joseph R Arron; Lin Pan; Amrita V Kamath; Eric G Stefanich

doi:10.1016/j.xphs.2023.07.005

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

J Pharm Sci. 2023 Nov;112(11):2910-2920. doi: 10.1016/j.xphs.2023.07.005. Epub 2023 Jul 8.

Authors

Rajbharan Yadav¹, Siddharth Sukumaran², Jeff Lutman², Mayur S Mitra³, Wendy Halpern³, Tianhe Sun⁴, A Francesca Setiadi⁵, Margaret Neighbors⁶, X Rebecca Sheng⁶, Victor Yip², Ben-Quan Shen², Chang Liu⁵, Lyrialle Han⁷, Ayse Meric Ovacik², Yan Wu⁸, Sara Glickstein⁹, Rebecca Kunder⁹, Joseph R Arron⁴, Lin Pan⁷, Amrita V Kamath², Eric G Stefanich¹⁰

Affiliations

¹ Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, USA. Electronic address: yadavr13@gene.com.
² Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, USA.
³ Safety Assessment, Genentech Inc., South San Francisco, CA, USA.
⁴ Immunology Discovery, Genentech Inc., South San Francisco, CA, USA.
⁵ BioAnalytical Sciences, Genentech Inc., South San Francisco, CA, USA.
⁶ Translational Medicine, Genentech Inc., South San Francisco, CA, USA.
⁷ Clinical Pharmacology, Genentech Inc., South San Francisco, CA, USA.
⁸ Antibody Engineering, Genentech Inc., South San Francisco, CA, USA.
⁹ Early Clinical Development, Genentech Inc, South San Francisco, CA, USA.
¹⁰ Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, USA. Electronic address: erics@gene.com.

PMID: 37429356
DOI: 10.1016/j.xphs.2023.07.005

Abstract

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.

Keywords: Anti-TGFβ3; Biomarker; Fibrotic diseases; First-in-human clinical trial; Gene expression; Healthy volunteers; Pharmacokinetics and pharmacodymics; Starting dose selection.