Recent advances in antibody-drug conjugate (ADC) technology have enabled the development of highly potent, tumor-targeted therapeutics with improved efficacy and safety. Sutro Biopharma, leveraging its site-specific and cell-free protein synthesis platform, has reported robust preclinical data for its pipeline of next-generation ADCs at the annual meeting of the American Association for Cancer Research (AACR), held April 17 – 22, 2026.
The highlights include the demonstration of superior antitumor activity of TRO-004 in tissue factor (TF)-expressing tumors, meaningful dose-dependent efficacy of STRO-006 and STRO-227 in solid tumor models, and presentation of a TROP2-targeted immunostimulatory ADC program in partnership with Astellas.
Development
Antibody-drug conjugates (ADCs) have transformed oncology by enabling the selective delivery of cytotoxic payloads to tumor cells. However, challenges persist with efficacy against heterogeneous and low-antigen tumors, treatment resistance, and systemic toxicity. Sutro Biopharma’s platform addresses these issues by enabling precise site-specific conjugation of single- or dual-payloads, optimizing the antibody, linker, and payload chemistry to improve pharmacokinetics, stability, and therapeutic index.
Preclinical Data Highlights
- STRO-004: A Next-Generation Tissue Factor (TF-) Targeted ADC
STRO-004 is a site-specific beta-glucuronidase-cleavable ADC with a stable linker and a DAR8 exatecan payload targeting tissue factor (TF). Tissue Factor (TF) is a transmembrane glycoprotein with tumor-selective expression that has been implicated in promoting tumor progression through enhanced tumor angiogenesis and metastasis, making it an ideal target for an antibody-drug conjugate (ADC). STRO-004 is engineered for enhanced plasma stability and pharmacokinetics (PK), which leads to improved efficacy and reduced off-target toxicity compared with 1st-generation TF-targeting ADCs. In preclinical studies, STRO-004 has demonstrated robust and consistent antitumor activity across a comprehensive panel of patient-derived xenograft (PDX) models representing multiple TF-expressing solid tumor types, including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), cervical, colorectal cancer (CRC), and pancreatic cancer (PDAC). At a clinically relevant single dose of 5 mg/kg, TRO-004 achieved remarkable disease control and tumor regression, outperforming benchmark ADCs. STRO-004’s favorable pharmacokinetic profile and the highest non-severely toxic dose (HNSTD) of 50 mg/kg suggest an expanded therapeutic window. In vitro studies revealed reduced cytotoxicity toward corneal and skin epithelial cells compared to approved TF-targeting ADCs, supporting a superior safety profile. Exploratory biomarker analyses suggest a mechanism of action involving bystander killing and immunogenic cell death, potentially enabling combination with immunotherapies. A Phase 1 clinical trial (NCT07227168) is ongoing, targeting high TF-expressing solid tumors. [1] [Poster] - STRO-006: Integrin β6-Targeted ADC
STRO-006 is an investigational ADC targeting integrin β6 (ITGb6), a protein highly expressed in various carcinomas with restricted normal tissue distribution. The ADC is composed of an ITGb6 targeted human IgG1 antibody conjugated to exatecan, a topoisomerase 1 inhibitor, via a β-glucuronidase-cleavable linker. The anti-ITGb6 antibody was discovered from a Fab ribosome display library using Sutro’s XpressCF+® system. The drug-linker is functionalized with dibenzylcyclooctyne (DBCO) and enables rapid, selective, site-specific conjugation to the azide-containing non-natural amino acid p-azidomethylphenylalanine (pAMF) incorporated into the antibody sequence using XpressCF+®. Preclinical studies show robust, dose-dependent antitumor activity at 5 mg/kg in models of non-small cell lung cancer (NSCLC), head and neck cancer, and pancreatic cancer. STRO-006 exhibits favorable pharmacokinetics and tolerability, with a stable drug-antibody ratio (DAR) of 8, and does not interfere with TGFβ signaling. IND submission is planned for 2026, followed by a Phase 1, first-in-human study to assess the safety and activity of STRO-006. [2] [Poster] - STRO-227: PTK7-Targeted Dual-Payload ADC
STRO-227, an investigational PTK7-targeting antibody-drug conjugate (ADC) generated using Sutro’s XpressCF+® cell-free protein synthesis platform (which enables the site-selective incorporation of non-natural amino acids), targets PTK7, a catalytically inactive, cell surface protein tyrosine kinase and a marker of tumor-initiating cancer stem cells, using a dual-payload strategy. The ADC incorporates both exatecan (topoisomerase I inhibitor) and monomethyl auristatin E (MMAE, a microtubule inhibitor), linked via a hydrophilic β-glucuronidase-cleavable linker, at defined DARs of 8 exatecan to 2 MMAE payloads (8:2). STRO-227 demonstrated robust, dose-dependent antitumor activity in triple-negative breast cancer (TNBC), ovarian cancer, and non-small cell lung cancer (NSCLC) models, with superior efficacy compared to single-payload ADCs. Pharmacokinetics and safety in non-human primates were favorable, with the highest non-severely toxic dose (HNSTD) comparable to established MMAE- and topoisomerase I-based single-payload ADCs, supporting further clinical development. An Investigational New Drug (IND) application for STRO-227 is expected in late 2026.[3][Poster] - Advancements in Dual-Payload ADCs and Combination Strategies
Sutro’s dual-payload ADC (dpADC) platform enables co-delivery of two distinct cytotoxic or synergistic payloads in a single, homogeneous molecule. Preclinical HER2-targeted dpADCs (exatecan/TOPO1i + monomethyl auristatin E) exhibited superior antitumor activity compared to single-payload ADCs and overcame resistance to single-payload ADCs in xenograft models at an 8:4 ratio. Notably, dpADCs that combine topoisomerase I inhibitors with DNA damage response inhibitors (PARPi or ATRi) exhibit synergistic cytotoxicity and minimize off-target toxicity, broadening the therapeutic window and enabling efficacy in models refractory to standard ADCs. To mimic the resistance observed in single-payload ADCs in the clinic, the researchers continuously dosed xenograft tumors with trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca) weekly until tumor progression. The trastuzumab deruxtecan-resistant tumors were then continuously dosed with an ADC with a monomethyl auristatin E payload until de novo resistance developed. Dual-resistant tumors were then treated with a dpADC, resulting in deep and durable anti-tumor responses. The study’s outcomes showed that even in tumors rendered resistant to both payloads (exatecan/TOPO1i + monomethyl auristatin E), the dpADC treatment achieved substantial tumor regression, demonstrating the potential for benefit in mono-payload ADC-refractory settings.[4][Poster] - TROP2-Targeted Immunostimulatory ADCs: Partnership with Astellas
Sutro’s collaboration with Astellas yielded ASP2998, a first-in-class Trophoblast cell surface antigen-2 (TROP2)-targeted immunostimulatory ADC (iADC) with dual payloads (cytotoxic + STING agonist) that combines cytotoxic and immune-stimulatory mechanisms to enhance antitumor efficacy. Preclinical results demonstrated potent efficacy, immune activation, and durable tumor immunity, with a favorable safety profile. ASP2998 is currently in early clinical development (NCT07287995). [5][6][Poster]
Meeting major unmet medical needs
The robust and consistent preclinical efficacy of Sutro’s ADC candidates across diverse solid tumor models, together with favorable safety and pharmacokinetics, highlight the potential of site-specific and dual-payload ADCs to address major challenges in cancer therapy. The flexibility of Sutro’s cell-free platform enables rapid iteration and optimization of ADCs for specific tumor targets and resistance mechanisms.
Sutro Biopharma’s next-generation ADCs demonstrate potent, durable, and broad-spectrum antitumor activity in preclinical models, with platform innovations supporting improved efficacy, safety, and resistance management. Ongoing and planned clinical trials will further define the therapeutic potential of these agents across solid tumor indications.
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Clinical trials
A Study of ASP2998 Given by Itself and Given With Standard Therapies in People With Solid Tumors – ClinicalTrials.gov ID NCT07287995
A Study of STRO-004 in Adults With Refractory/Recurrent Metastatic Cancer – ClinicalTrials.gov ID NCT07227168
Highlights of prescribing information
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
References
[1] Sommerhalder D, Reuss J, Pappas L, Salkeni MA, Vandross A, Henry JT, Hernandez G, Mangeshkar M, Oliver J, Patel MR. STRO-004 ST1: Phase 1 open-label study to evaluate safety, pharmacokinetics, and preliminary anti-tumor activity of STRO-004 in adults with refractory/recurrent metastatic solid tumors. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research; 2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr CT077 / 8
[2] Doshi KA, Armstrong S, Kim E, Shen D, Zhou S, Pena R, Yuan R, Armanini M, Vuillemenot B, Li X, Xu G, Bajjuri K, Wen M, Hanson J, Tran C, Gakhal A, Gross G, Yin G, Rubas W, Hernandez G, Calarese D, Gerber HP, Yam A. STRO-006: An Integrin beta-6-targeting ADC demonstrates favorable safety profile and potent antitumor activity in preclinical solid tumors. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research; 2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr 1713 / 10.
[3] Calarese D, Doshi K, Gross G, Vuillemenot B, Li X, Armanini M, Xu G, Wen M, Bajjuri K, Yin G, Rubas W, Yam A, Gerber H. Preclinical characterization of STRO-227: A PTK7-targeting dual-payload ADC with topoisomerase 1 and tubulin inhibitors. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research;
2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr 1695 / 24
[4] Matcham A, Yuan R, Vuillemenot B, Pena R, Park Y, Yu A, Hanson J, Tran C, Li X, Wen M, Calarese D, Rubas W, Bajjuri K, Xu G, Yam A, Gerber H. The HER2-targeting dual-payload antibody-drug conjugate combining a topoisomerase I inhibitor and a microtubule inhibitor demonstrates superior efficacy and overcomes resistance to single-payload ADCs in xenograft models. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research; 2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr 1685 / 14
[5] Bajjuri K, Yuan R, Calarese D, Pena R, Singh R, Park Y, Tran C, Yu A, Li X, Xu G, Zhou Y, Vuillemenot B, Rubas W, Hernandez G, Yam A, Yin G, Gerber HP. Sutro’s site-specific dual-payload ADCs combining TOPO1i and DNA damage response inhibitors to enhance efficacy, overcome resistance, and improve safety. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research; 2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr 4436 / 14
[6] Orr M, Chaen T, Shibata M, Ishikawa N, Matsuda T, Fujita Y, Haggerty G, Ochiai Y, Tanaka H, Akaiwa M, Li X, Doshi KA, Mahauad-Fernandez W, Bajjuri K, Yin G. ASP2998, a TROP2-targeted immunostimulatory antibody drug conjugate (iADC) with dual payloads, demonstrates potent efficacy and a favorable safety profile in nonclinical models. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research; 2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr 1289
Featured image: San Diego, CA – The AACR 2026 Annual Meeting – Photo courtesy 2026 © AACR/Scott Morgan.
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