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A homogeneous high-DAR antibody-drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides.

ABSTRACT: The antibody-drug conjugate (ADC) is a well-validated modality for the cell-specific delivery of small molecules with impact expanding rapidly beyond their originally-intended purpose of treating cancer. However, antibody-mediated delivery (AMD) remains inefficient, limiting its applicability to targeting highly potent payloads to cells with high antigen expression. Maximizing the number of payloads delivered per antibody is one key way in which delivery efficiency can be improved, although this has been challenging to carry out; with few exceptions, increasing the drug-to-antibody ratio (DAR) above ∼4 typically destroys the biophysical properties and in vivo efficacy for ADCs. Herein, we describe the development of a novel bioconjugation platform combining cysteine-engineered (THIOMAB) antibodies and recombinant XTEN polypeptides for the unprecedented generation of homogeneous, stable "TXCs" with DAR of up to 18. Across three different bioactive payloads, we demonstrated improved AMD to tumors and Staphylococcus aureus bacteria for high-DAR TXCs relative to conventional low-DAR ADCs.

SUBMITTER: Zacharias N

PROVIDER: S-EPMC8926172 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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A homogeneous high-DAR antibody-drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides.

Zacharias Neelie N Podust Vladimir N VN Kajihara Kimberly K KK Leipold Douglas D Del Rosario Geoffrey G Thayer Desiree D Dong Emily E Paluch Maciej M Fischer David D Zheng Kai K Lei Corinna C He Jintang J Ng Carl C Su Dian D Liu Luna L Masih Shabkhaiz S Sawyer William W Tinianow Jeff J Marik Jan J Yip Victor V Li Guangmin G Chuh Josefa J Morisaki J Hiroshi JH Park Summer S Zheng Bing B Hernandez-Barry Hilda H Loyet Kelly M KM Xu Min M Kozak Katherine R KR Phillips Gail Lewis GL Shen Ben-Quan BQ Wu Cong C Xu Keyang K Yu Shang-Fan SF Kamath Amrita A Rowntree Rebecca K RK Reilly Dorothea D Pillow Thomas T Polson Andrew A Schellenberger Volker V Hazenbos Wouter L W WLW Sadowsky Jack J

Chemical science 20220128 11

The antibody-drug conjugate (ADC) is a well-validated modality for the cell-specific delivery of small molecules with impact expanding rapidly beyond their originally-intended purpose of treating cancer. However, antibody-mediated delivery (AMD) remains inefficient, limiting its applicability to targeting highly potent payloads to cells with high antigen expression. Maximizing the number of payloads delivered per antibody is one key way in which delivery efficiency can be improved, although this ...[more]

PMID: 35414872

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Project description:DSTA4637S, a novel THIOMAB™ antibody-antibiotic conjugate (TAC) against Staphylococcus aureus (S. aureus), is currently being investigated as a potential therapy for complicated S. aureus bloodstream infections. DSTA4637S is composed of a monoclonal THIOMABTM IgG1 recognizing S. aureus linked to a rifamycin-class antibiotic (dmDNA31) via a protease-cleavable linker. The pharmacokinetics (PK) of DSTA4637A (a liquid formulation of DSTA4637S) and its unconjugated antibody MSTA3852A were characterized in rats and monkeys. Systemic concentrations of three analytes, total antibody (TAb), antibody-conjugated dmDNA31 (ac-dmDNA31), and unconjugated dmDNA31, were measured to describe complex TAC PK in nonclinical studies. In rats and monkeys, following intravenous administration of a single dose of DSTA4637A, systemic concentration-time profiles of both TAb and ac-dmDNA31 were bi-exponential, characterized by a short distribution phase and a long elimination phase as expected for a monoclonal antibody-based therapeutic. Systemic exposures of both TAb and ac-dmDNA31 were dose proportional over the dose range tested, and ac-dmDNA31 cleared 2-3 times faster than TAb. Unconjugated dmDNA31 plasma concentrations were low (<4 ng/mL) in every study regardless of dose. In this report, an integrated semi-mechanistic PK model for two analytes (TAb and ac-dmDNA31) was successfully developed and was able to well describe the complicated DSTA4637A PK in mice, rats and monkeys. DSTA4637S human PK was predicted reasonably well using this model with allometric scaling of PK parameters from monkey data. This work provides insights into PK behaviors of DSTA4637A in preclinical species and informs clinical translatability of these observed results and further clinical development. Abbreviations: ADC: Antibody-drug conjugate; AUCinf: time curve extrapolated to infinity; ac-dmDNA31: antibody-conjugated dmDNA31; Cmax: maximum concentration observed; DAR: drug-to-antibody ratio; CL: clearance; CLD: distribution clearance; CL1: systemic clearance of all DAR species; kDC: deconjugation rate constant; PK: Pharmacokinetics; IV: Intravenous; IgG: Immunoglobulin G; mAb: monoclonal antibody; S. aureus: Staphylococcus aureus; TAC: THIOMABTM antibody-antibiotic conjugate; TDC: THIOMABTM antibody-drug conjugate; TAb: total antibody; t1/2, λz: terminal half-life; vc linker: valine-citrulline linker; Vss: volume of distribution at steady state; Vc: volume of distribution for the central compartment; Vp: the volume of distribution for the peripheral compartment.

Dataset Information

A homogeneous high-DAR antibody-drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides.

Publications

A homogeneous high-DAR antibody-drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides.

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