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Sutro’s new ADC development approach: nnAA insertion based on CFPS
Release date:
2024-08-27
Recently, Perotin Bio announced that it is offering protein expression services featuring site-specific incorporation of non-canonical amino acids, leveraging its proprietary cell-free protein synthesis (CFPS) platform, thereby attracting widespread attention within the industry.
Why is the incorporation of non‑natural amino acids (nnAAs) so important? In which fields can they demonstrate their full potential?
Today, let’s explore how Sutro Biopharma, an internationally renowned company in drug discovery, development, and manufacturing, leverages nnAA incorporation to advance the research and development of antibody–drug conjugates.
Antibody-Drug Conjugate
Antibody–drug conjugates (ADCs) consist of a monoclonal antibody, a potent cytotoxic agent, and a linker. The linker covalently attaches the cytotoxic payload to the antibody, enabling the antibody’s tumor‑specific binding to deliver the cytotoxic agent directly to tumor cells. This targeted recognition increases the intratumoral concentration of the cytotoxic agent while minimizing its exposure in normal tissues and organs, thereby enhancing antitumor efficacy and reducing systemic toxicity. [1]
Schematic diagram of the ADC mechanism of action [2]
ADC conjugation methods primarily include non‑site‑specific conjugation and site‑specific conjugation. Non‑site‑specific conjugation was the approach used in early ADC research; it generates a heterogeneous mixture of ADCs with varying drug payloads attached at different antibody sites, which can compromise ADC toxicity, stability, and efficacy. Site‑specific conjugation typically requires engineering or modification of the antibody to enable attachment of cytotoxic payloads at defined locations, thereby enhancing ADC homogeneity, improving pharmacokinetics, and widening the therapeutic window. Amino acid (aa) insertion, as a form of site‑specific conjugation, allows the introduction of specialized side‑chain moieties that create convenient, well‑defined conjugation sites on the antibody surface, enabling efficient and selective coupling.
Sutro Biopharma’s Xpress CF+ platform
Sutro Biopharma is focused on developing site-specific and next-generation antibody–drug conjugates by leveraging its proprietary integrated cell-free protein synthesis platform, Xpress CF, and its non-canonical amino acid–based site-specific conjugation technology platform, Xpress CF+.
Sutro designed and synthesized an optimized p‑azido‑methyl‑L‑phenylalanine (pAMF); using a high‑throughput screening platform based on cell‑free protein expression, they identified a novel variant of the M. jannaschii tyrosyl‑tRNA synthetase (TyrRS) that exhibits high activity and specificity toward pAMF. Subsequently, they expressed a trastuzumab variant incorporating pAMF in a cell‑free protein expression system and engineered a DBCO‑PEG‑MMAF drug‑linker conjugate capable of covalently attaching pAMF‑incorporated antibodies to the drug. This approach enabled the successful production of site‑specifically pAMF‑modified antibody–drug conjugates with a drug‑to‑antibody ratio (DAR) ranging from 1.2 to 1.9. [3]
Antibody–drug conjugates with pAMF site-specific insertion
Based on the Xpress CF and Xpress CF+ technology platforms, Sutro currently has three ADCs in development—STRO‑001, STRO‑002, and STRO‑003. In 2021, Sutro entered into a collaboration with the Chinese biopharmaceutical company Yehui Pharma, granting Yehui exclusive rights to develop and commercialize STRO‑001 in Greater China. In 2022, Sutro partnered with Astellas, under which Astellas will leverage Sutro’s technology platforms to advance three novel ADC candidates. This April, Sutro and the French pharmaceutical giant Ipsen jointly announced a global, exclusive license agreement for Sutro’s investigational product STRO‑003, with total potential value up to US$900 million. As a leader in the cell-free protein space, Sutro’s groundbreaking site-specific incorporation of non‑natural amino acids via its cell‑free protein expression platform has garnered widespread attention, ushering in transformative advances across healthcare and other fields.
nnAA insertion service from Perotin Bio
Cell-free protein expression systems offer significant advantages in the field of non-canonical amino acid incorporation:
(1) Cell-free systems lack a cellular membrane barrier, thereby circumventing the issue of nnAA selectivity.
(2) Cell-free systems are not subject to the cytotoxic effects that nnAAs may exert.
(3) It facilitates the elimination of endogenous competition, thereby promoting the incorporation of non‑natural amino acids.
Perotin Bio, as China’s first institution to offer services related to the incorporation of non‑natural amino acids based on a fully proprietary cell‑free protein expression platform, currently provides the following services:
(1) Site-specific incorporation of pAcF and pAzF: p‑Acetylphenylalanine (pAcF) and p‑Azidophenylalanine (pAzF) can serve as coupling reaction sites for antibody–drug conjugation, enabling precise control of the drug-to-antibody ratio.
(2) Non‑natural amino acid incorporation assay: Based on the customer‑provided aminoacyl‑tRNA synthetase, tRNA, and non‑natural amino acid, Perotin Bio offers assay services using a cell‑free platform.
References:
[1] Chen Hu, Zhang Xinling, Kong Nana, et al. Clinical research progress and challenges of antibody–drug conjugates based on site-specific conjugation technology [J]. Pharmaceutical Progress, 2021, 45(03):167-179.
[2]HAFEEZ U, PARAKH S, GAN H K, et al. Antibody drug conjugates for cancer therapy. Molecules. MDPI AG, 2020, 25(20).
[3]ZIMMERMAN E S, HEIBECK T H, GILL A, et al. Production of site-specific antibody-drug conjugates using optimized non-natural amino acids in a cell-free expression system. Bioconjugate Chemistry, 2014, 25(2): 351-361.
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