Preclinical evaluation of a novel antibody-drug conjugate targeting DR5 for lymphoblastic leukemia therapy

Abstract

Acute lymphoblastic leukemia (ALL) is an aggressive hematological neoplasm resulting from immature lymphoid precursors. An antibody-drug conjugate (ADC), coupling a small molecule covalently with a targeting antibody, can specifically kill tumor cells. Death receptor 5 (DR5) is considered as a promising anti-tumor drug target. In this study, we describe the preclinical evaluation of a novel DR5-targeting ADC (Oba01) as a potential therapeutic against ALL. Oba01 utilizes anti-DR5 humanized monoclonal antibody (zaptuzumab) coupled via a cleavable linker to monomethyl auristatin E (MMAE). Oba01 can specifically bind to DR5 on the tumor cells and transfer into lysosome via DR5-mediated endocytosis. It then effectively releases the MMAE, which can bind to the tubulin and prevent its aggregation, thereby leading to a significant inhibition of proliferation and cell death in tumor cells. Additionally, Oba01 displays significant dose-dependent tumoricidal activity in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. More importantly, toxicity analysis of Oba01 showed a favorable safety profile, and pharmacokinetic analysis illustrated an excellent stability and tolerability in rats and cynomolgus monkeys. Taken together, our data conclusively demonstrate that Oba01 is an attractive candidate for further clinical trials in DR5-positive ALL patients.

Combined therapy of dabrafenib and an anti-HER2 antibody–drug conjugate for advanced BRAF-mutant melanoma

“…Antibody-drug conjugates (ADCs) serve as a potentially promising therapeutic approach for the treatment of solid tumors and hematologic malignancies. ADCs combine antibody-associated antigen specificity with cytotoxic antitumor effects, thereby maximizing efficacy and minimizing systemic toxicity [27][28][29][30][31]. Successful examples include Herceptin (trastuzumab), a humanized monoclonal antibody for targeting HER-2-positive breast cancer [32,33], and adotrastuzumab emtansine (T-DM1), a second generation ADC composed of trastuzumab conjugated to maytansoinoid emtansine (DM1).…”

Therapeutic efficacy of a MMAE-based anti-DR5 drug conjugate Oba01 in preclinical models of pancreatic cancer

“…Similar to Zapadcine-1, Oba01 significantly inhibits tumor growth in DR5-positive lymphocytic leukemia in vitro and in vivo in a dose-dependent manner. Its safety window, when compared with Zapadcine-1, was significantly larger in both acute and chronic toxicity studies in rats and cynomolgus monkeys, suggesting that Oba01 has excellent preclinical tolerability and a good safety profile [ 22 ]. Therefore, it can be considered an optimistic prospect for subsequent clinical development.…”

Subcellular Proteome Analysis Reveals Apoptotic Vulnerability of T-Cell Acute Lymphoblastic Leukemia

“…Due to their tumor-specific cytotoxicity, several humanized DR5-agonistic monoclonal antibodies have been developed and approved to be able to induce apoptosis in various tumor models [5][6][7][8][9][10]. Indeed, a number of DR5 targeting agents, including multivalent antibodies, antibody-drug conjugates, recombinant TRAIL variants, and small molecules are currently under active clinical evaluations with promising results in a number of cancers, demonstrating the therapeutic value of DR5 [11][12][13][14][15][16]. Notably, the human T-ALL cell lines such as Jurkat are among the most sensitive cells towards in vitro and in vivo cytotoxicity of anti-DR5 antibodies, providing initial support for the feasibility of their applications in T-ALL treatments.…”