Bispecific c-Kit/CD203c Antibodies for Selective Mast Cell Depletion
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Solution Overview
Problem
Existing treatments for chronic inflammatory diseases targeting mast cell survival receptor c-Kit lead to on-target dose-limiting bone marrow suppression due to indiscriminate inhibition, and there is a lack of granulocyte cell-selective drugs for effective mast cell depletion.
Innovation Solution
Development of bispecific proteins with specific binding domains for c-Kit and CD203c, utilizing a common light chain format to enhance manufacturing efficiency and avoid myelosuppression, allowing targeted mast cell depletion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If standard antibodies with high affinity target engagement are used to inhibit c-Kit, then mast cell depletion effectiveness is improved, but bone marrow suppression worsens
Solution Approach 1:
The patent applies local quality by making the antibody's binding properties state-dependent: the bispecific antibody binds to c-Kit with high affinity only when CD203c is also present on the cell surface (activated state), while showing reduced binding to resting c-Kit+ cells. This selective binding based on local molecular context (presence of CD203c) enables targeted mast cell depletion without affecting bone marrow cells that express c-Kit but not CD203c
Solution Approach 2:
The patent uses CD203c as an intermediary marker to mediate selective target engagement. The bispecific antibody requires simultaneous binding to both c-Kit and CD203c for stable target engagement, using CD203c expression as an intermediary condition that distinguishes activated mast cells from other c-Kit+ cells. This intermediary requirement prevents off-target effects on bone marrow suppression
2Reliability
If indiscriminate c-Kit inhibition is used to deplete mast cells, then mast cell depletion is achieved, but selectivity for granulocyte cells worsens
Solution Approach 1:
The patent implements local quality by creating a dual-binding requirement where the antibody only achieves stable binding to c-Kit when CD203c is locally present on the cell surface. This local molecular context (CD203c co-expression) serves as a quality filter that distinguishes activated mast cells from other granulocyte precursors in the bone marrow, achieving both depletion effectiveness and cell-type selectivity
3Strength
If bivalent engagement with standard antibodies is used, then target engagement affinity is improved, but adverse events worsen
Solution Approach 1:
The patent applies local quality by making the bivalent engagement state-dependent: the bispecific antibody achieves high-affinity bivalent binding only when both c-Kit and CD203c are present on the target cell surface (activated mast cells). When CD203c is absent (as in bone marrow cells), the antibody cannot form stable bivalent engagement, reducing affinity to monovalent or no binding. This local molecular context requirement converts the strength advantage into selective action
Solution Approach 2:
The patent inverts the conventional approach by using the presence of CD203c as an enabling condition for high-affinity binding rather than using high-affinity binding indiscriminately. Instead of assuming high affinity always leads to effective targeting, the invention makes high affinity contingent upon CD203c co-expression, thereby inverting the causality between binding strength and therapeutic effect
Data Source
AI summary
Provided herein are bispecific antigen-binding molecules that bind to c-Kit and CD203c. Further provided herein are therapeutic uses of and methods of producing such molecules and related pharmaceutical compositions, nucleic acid molecules, expression vectors and host cells.