A novel anti-DR5 antibody-drug conjugate possesses a high-potential therapeutic efficacy for leukemia and solid
Shuyong Zhang1,2, Chao Zheng1, Wan Zhu1
1Yantai Obioadc Biomedical Technology Ltd., Yantai, China.
Abstract:
It is well known that tumor necrosis factor-related apoptosis inducing ligand receptor 1 or 2 (DR4/DR5) is specifically expressed in various tumor cells, but less or no expression in most normal cells. Many first generations of TRAIL agonists including recombinant preparations of TRAIL, agonistic antibodies against DR4/DR5 have been developed in phase I/II clinical trials for cancer therapy. However, the outcomes of clinical trials by using DR4/DR5 agonist mono-therapy were disappointed even though the safety profile was well tolerance. In the present study, we report an anti-DR5 antibody-drug conjugate (ADC, named as Zapadcine-1) possesses a higher potential for the therapy of lymphocyte leukemia and solid cancers. Methods: Zapadcine-1 was made by a fully humanized DR5-specific monoclonal antibody (Zaptuzumab) coupled via a cleavable linker to a highly toxic inhibitor of tubulin, monomethyl auristatin D (MMAD), by using ThioBridge technology. Cytotoxicity of the ADC in various tumor cells was identified by luminescent cell viability assay and the efficacy in vivo was determined in cells derived xenografts (CDX) of Jurkat E6-1, BALL-1, Reh, and patient derived xenografts (PDX) of human acute leukemia. Preliminary safety evaluation was carried out in rat and monkey. Results: Zapadcine-1 possesses a similar binding ability to the death receptor DR5 as the naked monoclonal antibody Zaptuzumab, and can be rapidly endocytosed into the lysosome of cancer cells. Zapadcine-1 specifically kills human lymphocyte leukemia cells and solid tumor cells, but not normal cells tested. More importantly, Zapadcine-1 drastically eliminates the xenografts in both CDX and PDX models of human acute leukemia. The excellent and comparable therapeutic efficacy is also observed in lung cancer NCI-H1975 CDX mouse model. The maximum-tolerated dose (MTD) of single injected Zapadcine-1 in rat and cynomolgus monkey shows an acceptable safety profile. Conclusion: These data demonstrate a promising anti-cancer activity, meriting further exploration of its potential as a novel cancer therapeutic agent, especially for the acute lymphocyte leukemia.
Insights
A novel antibody-drug conjugate, Zapadcine-1, shows significant potential for treating acute lymphocyte leukemia and solid cancers by selectively targeting tumor necrosis factor receptor 1 or 2 (DR4/DR5). This targeted therapy demonstrates potent anti-cancer activity with an acceptable safety profile in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Death receptors DR4/DR5 are expressed on tumor cells but minimally on normal cells.
- Previous TRAIL agonists showed limited success in monotherapy for cancer treatment.
- There is a need for more effective targeted cancer therapies.
Purpose of the Study:
- To evaluate the therapeutic potential of Zapadcine-1, an anti-DR5 antibody-drug conjugate (ADC).
- To assess the efficacy and safety of Zapadcine-1 in preclinical models of leukemia and solid tumors.
Main Methods:
- Zapadcine-1 was constructed using a humanized anti-DR5 antibody (Zaptuzumab) linked to a cytotoxic agent (MMAD) via ThioBridge technology.
- Cytotoxicity was assessed using luminescent cell viability assays.
- In vivo efficacy was evaluated in cell-derived xenografts (CDX) and patient-derived xenografts (PDX) models of acute leukemia and lung cancer.
Main Results:
- Zapadcine-1 effectively binds to DR5 and is internalized by cancer cells.
- The ADC specifically eliminates lymphocyte leukemia and solid tumor cells, sparing normal cells.
- Zapadcine-1 demonstrated significant tumor regression in acute leukemia xenograft models and lung cancer models, with an acceptable safety profile.
Conclusions:
- Zapadcine-1 exhibits promising anti-cancer activity, particularly against acute lymphocyte leukemia.
- The targeted nature and efficacy of Zapadcine-1 warrant further investigation as a novel cancer therapeutic agent.
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