Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody–Drug Conjugate for the Treatment of Cancer

Sep 24, 2026

Antibody–drug conjugates (ADCs) enable targeted delivery of cytotoxic payloads to tumors, with their activity and safety shaped by antibody structure, linker, payload, and conjugation, including the drug-to-antibody ratio (DAR). To optimize ADCs for specific target antigens, a novel Dolasynthen (DS) platform using auristatin hydroxypropylamide supports precise DAR-ranging and site-specific conjugation. The resulting XMT-1660 is a site-specific DS DAR6 B7-H4-targeted ADC that produced complete regressions in multiple breast and ovarian xenograft models and a PD-1–refractory syngeneic model, with activity correlating with B7-H4 expression and early clinical initiation in phase I (NCT05377996).

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

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Introduction

Antibody–drug conjugates and platform diversity

ADC optimization and determinants of activity/safety

Rationale for targeting B7-H4 and avoiding PD-L1 overlap

FIRST DISCLOSURE Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody–Drug Conjugate for the Treatment of Cancer Dorin Toader, Shawn P. Fessler, Scott D. Collins, Patrick R. Conlon, Reddy Bollu, Kalli C. Catcott, Chen-Ni Chin, Anouk Dirksen, Bingfan Du, Jeremy R. Duvall, Stacy Higgins, Mariya V. Kozytska, Kamela Bellovoda, Chelsey Faircloth, David Lee, Fu Li, Liuliang Qin, Caitlin Routhier, Pamela Shaw, Cheri A. Stevenson, Jason Wang, Phonphimon Wongthida, Elena Ter-Ovanesyan, Elizabeth Ditty, Stephen P. Bradley, Ling Xu, Mao Yin, Alexandr V. Yurkovetskiy, Rebecca Mosher, Marc Damelin, and Timothy B. Lowinger |
ABSTRACT | | | --- | --- | | ◥
Antibody–drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety proﬁle of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well asthe number ofpayload drugs per antibody[drug-to-antibody ratio (DAR)] . To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-speciﬁc conjugation. We used the new platform to optimize an ADC that targets B7-H4 ( VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660is a site-speciﬁcDS DAR6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory toPD-1immune checkpoint inhibition. Ina panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently | entered clinical development in a phase I study (NCT05377996) inpatients with cancer.

B7-H4 ( VTCN1) is a plasma membrane protein expressed in multiple tumor types, including breast cancer, ovarian cancer, and endometrial cancer, with limited expression in normal tissues (6–8) . Accordingly, preclinical studies suggested that B7-H4 could be amenable to an ADC approach (8, 9) as well as to other therapeutic modalities (9, 10) . B7-H4 has been reported to have an immunesuppressive function (11–14), and its expression in tumors has been associated with a lower frequency of tumor-inﬁltrating immune cells (7, 15) . In a mouse tumor model, B7-H4 knockout was associated with increased antitumor immune response, reduced metastasis, and increased survival (16) .
Strikingly, B7-H4 expression in tumors has minimal overlap with PD-L1 (also known as B7-H1) expression (17–19), which may reﬂect functional redundancy in inhibiting antitumor immunity. Consequently, in B7-H4þ tumors where PD-L1 expression is absent or low and PD-(L)1 immune checkpoint inhibitors may not be effective, aB7-H4 targeted agent may be an effective treatment option. The nonoverlapping expression proﬁles likely rooted in functional redundancy also provide a rationale for the potential beneﬁt of combining B7-H4 and PD-L1 targeted therapies, to prevent tumors from escaping therapy by switching between these immunosuppressive ligands.
The pharmacology of an ADC has been shown to depend not only on the antibody, linker and payload, but also the method and antibody site of conjugation (20) . An additional factor that impacts the pharmacology of ADCsis the number of payload drugs per antibody[drugto-antibody ratio (DAR)], that balances distribution of the drug to | | Introduction
Antibody–drug conjugates (ADCs) constitute a therapeutic modality that achieves targeted delivery to cells or tissues of interest by conjugating a payload drug to an antibody (1, 2) . ADCs have been developed predominantly in oncology, and currently in the United States, there are 12 approved ADCs built on 8 distinct linker-payload platforms, all of which employ a cytotoxic payload. More recently, in early clinical developmen

FAQs

What role does DAR and conjugation method play in ADC performance?

ADC activity and safety depend on antibody, payload, linker, conjugation method, and DAR. The optimal DAR is influenced by target expression, internalization rate, tumor architecture, and platform characteristics.

Why is B7-H4 considered a promising ADC target?

B7-H4 is a plasma membrane protein expressed across multiple tumors with limited normal tissue expression. Its immunosuppressive function and minimal overlap with PD-L1 suggest ADCs targeting B7-H4 may work when PD-L1-based checkpoint inhibition is ineffective.

What preclinical results support XMT-1660 as a B7-H4-targeted ADC?

XMT-1660 induced complete tumor regressions in breast and ovarian xenograft models and in a syngeneic breast model refractory to PD-1 checkpoint inhibition. In a panel of breast cancer PDXs, activity correlated with B7-H4 expression.

Sep 24, 2026

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