DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody–Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models

Abstract

B7-H3 is overexpressed in various solid tumors and has been considered as an attractive target for cancer therapy. Here, we report the development of DS-7300a, a novel B7-H3–targeting antibody–drug conjugate with a potent DNA topoisomerase I inhibitor, and its in vitro profile, pharmacokinetic profiles, safety profiles, and in vivo antitumor activities in nonclinical species. The target specificity and species cross-reactivity of DS-7300a were assessed. Its pharmacologic activities were evaluated in several human cancer cell lines in vitro and xenograft mouse models, including patient-derived xenograft (PDX) mouse models in vivo. Pharmacokinetics was investigated in cynomolgus monkeys. Safety profiles in rats and cynomolgus monkeys were also assessed. DS-7300a specifically bound to B7-H3 and inhibited the growth of B7-H3–expressing cancer cells, but not that of B7-H3–negative cancer cells, in vitro. Additionally, treatment with DS-7300a and DXd induced phosphorylated checkpoint kinase 1, a DNA damage marker, and cleaved PARP, an apoptosis marker, in cancer cells. Moreover, DS-7300a demonstrated potent in vivo antitumor activities in high–B7-H3 tumor xenograft models, including various tumor types of high–B7-H3 PDX models. Furthermore, DS-7300a was stable in circulation with acceptable pharmacokinetic profiles in monkeys, and well tolerated in rats and monkeys. DS-7300a exerted potent antitumor activities against B7-H3–expressing tumors in in vitro and in vivo models, including PDX mouse models, and showed acceptable pharmacokinetic and safety profiles in nonclinical species. Therefore, DS-7300a may be effective in treating patients with B7-H3–expressing solid tumors in a clinical setting.

Targeting DNA methylation and B7-H3 in RB1-deficient and neuroendocrine prostate cancer

“…6B). We confirmed that B7-H3 is expressed in the majority of prostate cancers, consistent with what has been previously described ( 32 , 33 ), and its expression ranges from low to high regardless of disease state (Fig. 6, B and C), with higher expression of B7-H3 being associated with inferior survival in patients with CRPC-Adeno ( P = 0.0206) (fig.…”

“…DS-7300a is composed of a humanized anti–B7-H3 monoclonal antibody, an enzymatically cleavable linker, and a potent DNA topoisomerase 1 inhibitor (DXd). The payload agent, DXd, causes apoptosis of cancer cells that express B7-H3 on their cell surface ( 33 ).…”

Target Antigen Attributes and Their Contributions to Clinically Approved Antibody-Drug Conjugates (ADCs) in Haematopoietic and Solid Cancers

“…One of these is sacituzumab govitecan (Trodelvy ® ), an anti-TROP-2 IgG1 antibody conjugated to SN-38, and the other is trastuzumab deruxtecan (Enhertu ® ), an anti-HER2 IgG1 antibody conjugated to deruxtecan (Dxd). SN-38 and Dxd are both related to the plant alkaloid camptothecin, and inhibit topoisomerase enzymes essential for the relaxation of supercoils during DNA replication, with Dxd being a higher-potency analogue of SN-38 [ 35 , 36 , 37 ]. Inhibition of topoisomerase function leads to DNA strand breaks during replication, followed by cell death through apoptosis [ 36 ].…”

Antibody-Drug Conjugates in Lung Cancer: Recent Advances and Implementing Strategies

“…105 DS-7300a is an ADC composed by a humanized B7-H3 IgG1 mAb and the topoisomerase I inhibitor payload DXd with a tetrapeptide-based cleavable linker (Fig 1). 106 The phase I/II first-in-human study enrolled 147 patients with tumors unselected for B7-H3 expression at doses of 4.8 mg/kg to 16.0 mg/kg once every 3 weeks (81 patients in dose escalation, 66 in 12.0 mg/kg dose expansion). 107 In the overall population, with a median of five prior treatment lines, ORR was 32% and DCR was 71.4%.…”