Rational engineering of degradation tail-driven CELMoD-antibody conjugates for precision malignancy therapy

Area of Science:

• Oncology
• Drug Discovery
• Molecular Biology

Background:

• Degrader-antibody conjugates (DACs) are a promising therapeutic strategy for hematological malignancies.
• Rational design frameworks for DACs are currently lacking.
• Cereblon E3 ligase modulators (CELMoDs) offer potential for novel conjugate development.

Purpose of the Study:

• To establish design strategies for antibody-degrader compatibility and conjugatability.
• To identify novel CELMoD payloads for DAC construction.
• To evaluate the efficacy and safety of novel DACs in hematological malignancies.

Main Methods:

• Systematic exploration of antibody-degrader compatibility.
• Development of a modular library for neo-substrate screening.
• Identification and conjugation of a novel CELMoD payload (I034).
• In vitro and in vivo evaluation of I034-based DACs compared to auristatin conjugates.

Main Results:

• Identified I034, a CELMoD payload with picomolar degradation activity and antiproliferative effects.
• Constructed I034-based DACs demonstrating superior efficacy and safety over auristatin conjugates.
• Achieved complete tumor eradication in vivo with CD38-targeting Dara-VA-I034 at low doses.
• Revealed distinct positive feedback regulation of CD38 conjugates, emphasizing payload-antigen compatibility.

Conclusions:

• The developed approach provides a framework for discovering CELMoD payloads for DACs.
• I034-based DACs show significant potential for treating multiple myeloma and other hematological malignancies.
• Payload-antigen compatibility is crucial for optimizing DAC efficacy and safety.