Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Oct 1;23(10):1483-1493.
doi: 10.1158/1535-7163.MCT-24-0087.

The Vedotin Antibody-Drug Conjugate Payload Drives Platform-Based Nonclinical Safety and Pharmacokinetic Profiles

Haley D Neff-LaFord  1 , Sarah A Carratt  1 , Christopher Carosino  1 , Nancy Everds  1   2 , Kristen A Cardinal  1 , Steven Duniho  1 , Melissa M Schutten  1 , Christopher Frantz  1 , Christina Zuch de Zafra  1 , Eric B Harstad  1
Affiliations

The Vedotin Antibody-Drug Conjugate Payload Drives Platform-Based Nonclinical Safety and Pharmacokinetic Profiles

Haley D Neff-LaFord et al. Mol Cancer Ther. .

Abstract

Nonclinical safety and pharmacokinetic data for monomethyl auristatin E (MMAE) and 14 vedotin antibody-drug conjugates (ADC) were evaluated to determine patterns of toxicity, consistency of pharmacokinetic results, and species differences between rats and monkeys. Most nonclinical toxicities were antigen-independent, common across ADCs, and included hematologic, lymphoid, and reproductive toxicity related to MMAE pharmacology. Hematologic toxicity was the dose-limiting toxicity (DLT) or predominant toxicity for the majority of vedotin ADCs in both species. Tissue expression of the targeted antigen of an ADC rarely correlated with DLT; only two ADCs had antigen-dependent skin DLTs. For two additional ADCs, antigen-dependent delivery of MMAE in the bone marrow may have exacerbated the antigen-independent hematologic DLT. The highest tolerated doses and pharmacokinetics were similar within a given species, with rats tolerating higher doses than monkeys. Studies longer than 1 month in duration detected the same or fewer toxicities than 1-month studies and had no additional findings that affected the human risk assessment. These data support opportunities to streamline ADC toxicity assessments without compromising human starting dose selection or target organ identification.

PubMed Disclaimer

Conflict of interest statement

H.D. Neff-LaFord, S.A. Carratt, C. Carosino, N. Everds, K.A. Cardinal, S. Duniho, M.M. Schutten, C. Frantz, C. Zuch de Zafra, and E.B. Harstad report being an employee of and having equity ownership in Seagen, Inc. (acquired by Pfizer in December 2023) at the time of this work. N. Everds also reports being a consultant for Seagen after her retirement.

Figures

Figure 1.
Figure 1.
Tolerated doses in cynomolgus monkeys dosed with vedotin ADCs. A, Schematic of a vedotin ADC. Vedotin ADCs consist of a mAb bound to MMAE by a protease-cleavable vc linker. B, Schematic demonstrating the two primary classifications of ADC toxicity used in this analysis: antigen dependent (changes in tissues expressing the target antigen) and antigen independent (changes that occurred with MMAE or the nonbinding vedotin ADC). C, Doses of vedotin ADCs evaluated in studies with either a Q1Wx4 or Q3Wx2 (SGN-B6A only) repeat dosing schedule. D, Doses of vedotin ADCs evaluated in ≥3-month duration studies. 2Q3Wx5: SGN-B6A and SGN-STNV. Q2Wx7: DV only. Studies following a Q3W schedule administered 4 (BV, PV, and PVsurr), 5 (LV, LIFA, and TV) or 9 (BV) total doses. LV, ladiratuzumab vedotin; PVsurr, PV surrogate; TV, tisotumab vedotin.
Figure 2.
Figure 2.
Vedotin ADCs have similar pharmacokinetics in monkeys regardless of target. A, Concentration–time profiles for TAb after a single dose at 3 mg/kg. B, Concentration–time profiles for MMAE after a single dose at 3 mg/kg. LV, ladiratuzumab vedotin.
See this image and copyright information in PMC

References

    1. Jain N, Smith SW, Ghone S, Tomczuk B. Current ADC linker chemistry. Pharm Res 2015;32:3526–40. - PMC - PubMed
    1. Doronina S. Monomethylvaline compounds capable of conjugation to ligands. U.S. Patent No. 7,498,298. US Patent Trademark Office; 2009.
    1. Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF, et al. . Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol 2003;21:778–84. - PubMed
    1. Seagen . PADCEV [package insert]; 2019.
    1. Seagen . ADCETRIS [package insert]; 2019.

LinkOut - more resources