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Preclinical development of mecbotamab vedotin (BA3011), a novel, AXL-specific conditional active biologic
Hwai Wen Chang1, Jing Wang1, Haizhen Liu1
1Research & Development, BioAtla Inc., San Diego, CA 92121, United States.
Background:
AXL, a tyrosine kinase receptor, is over-expressed in many solid and hematologic cancers, promoting progression and poor clinical outcomes. It also contributes to resistance against chemotherapeutic agents, especially tyrosine kinase inhibitors, by upregulating AXL signaling or switching oncogenic pathways. These factors make AXL an attractive therapeutic target. However, early attempts with naked antibody therapies failed due to the high doses need for efficacy, and antibody-drug conjugates (ADCs) targeting AXL were hindered by off-tumor toxicities due to its expression on normal tissues.
Methods:
To address these issues, we developed a novel, conditionally active biologic ADC, mecbotamab vedotin (BA3011), which selectively binds to AXL in the acidic tumor microenvironment. In healthy tissue, binding to AXL is substantially diminished due to a powerful selection mechanism utilizing naturally occurring, physiological chemicals referred to as Protein-associated Chemical Switches. BA3011 was tested in vitro and in vivo against AXL expressing cancer cells.
Results:
Mecbotamab vedotin demonstrates the expected AXL, tumor-specific binding properties and effectively induced lysis of AXL-positive cancer cell lines in vitro. In vivo, mecbotamab vedotin exhibited potent and lasting antitumor effects in human cancer xenograft mouse models. Furthermore, in nonhuman primates, mecbotamab vedotin demonstrated excellent tolerability at doses of up to 5 mg/kg and maintained linker-payload stability in vivo.
Conclusions:
These findings indicate that mecbotamab vedotin has the potential to be a robust and less toxic therapeutic agent, offering promise as a treatment for patients with AXL-positive cancers.
Insights
Mecbotamab vedotin is a novel antibody-drug conjugate that selectively targets AXL in tumors. This new therapy shows potent anti-cancer effects and improved safety, offering hope for AXL-positive cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- AXL receptor tyrosine kinase is over-expressed in various cancers, correlating with disease progression and therapeutic resistance.
- AXL signaling contributes to chemotherapy resistance, particularly against tyrosine kinase inhibitors.
- Previous AXL-targeted therapies, including naked antibodies and antibody-drug conjugates (ADCs), faced challenges with efficacy and off-tumor toxicity due to AXL expression on normal tissues.
Purpose of the Study:
- To develop a novel, conditionally active antibody-drug conjugate (ADC) targeting the AXL receptor.
- To engineer an ADC with selective binding in the tumor microenvironment to mitigate off-tumor toxicities.
- To evaluate the efficacy and safety of the novel ADC, mecbotamab vedotin (BA3011).
Main Methods:
- Development of mecbotamab vedotin (BA3011), a conditionally active biologic ADC utilizing Protein-associated Chemical Switches for tumor-specific AXL binding.
- In vitro testing against AXL-expressing cancer cell lines to assess binding and cell lysis.
- In vivo studies in human cancer xenograft mouse models to evaluate antitumor efficacy.
- Nonhuman primate studies to assess tolerability and linker-payload stability.
Main Results:
- Mecbotamab vedotin exhibited specific binding to AXL within the tumor microenvironment and induced effective lysis of AXL-positive cancer cells in vitro.
- Potent and sustained antitumor effects were observed in vivo in human cancer xenograft models.
- Excellent tolerability was demonstrated in nonhuman primates, with no observed toxicity at doses up to 5 mg/kg, and stable linker-payload integrity.
Conclusions:
- Mecbotamab vedotin demonstrates tumor-specific AXL binding and potent anti-cancer activity.
- The conditional activation mechanism significantly reduces off-tumor toxicity, enhancing the therapeutic window.
- Mecbotamab vedotin represents a promising, less toxic therapeutic candidate for treating patients with AXL-positive cancers.
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