Variant CD3-Binding Domains for Multispecific Antibodies
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Solution Overview
Problem
Current multispecific molecules targeting CD3 and disease antigens can be too potent, leading to excessive cytokine release, which limits their therapeutic window in treating cancers and infectious diseases.
Innovation Solution
Development of variant CD3-Binding Domains with altered affinity for CD3, incorporated into multispecific binding molecules, which reduce cytokine release and enhance targeted killing of disease antigen-expressing cells, while maintaining therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If reference CD3-Binding Domains are used in multispecific molecules, then potent CD3 binding and target cell killing are achieved, but excessive cytokine release occurs
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid residues in the CDR regions of CD3-Binding Domains to alter binding affinity. Specific substitutions (e.g., H100Q, H100R, H100E, H100D, H100K, H100F, H100P, H100M, H100G, H100A, H100C, H100W, H100Y, H100V, H100S, H100X, H100N, H100I, H100L, H100T, H100F, H100R, H100Q, H100P, H100M, H100G, H100A, H100C, H100W, H100Y, H100V, H100S, H100X, H100N, H100I, H100L, H100T) in the CDRH1 domain and corresponding changes in CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 domains create variant CD3-Binding Domains with reduced affinity for CD3, thereby decreasing cytokine release while preserving target cell killing capability
Solution Approach 2:
The patent applies local quality by making site-specific amino acid substitutions only in the CDR regions (complementarity determining regions) of the CD3-Binding Domain, while leaving the rest of the antibody structure intact. This localized modification approach allows precise control over CD3 binding affinity without affecting other functional regions of the multispecific molecule
2Object-generated harmful factors
If CD3 binding affinity is reduced to lower cytokine release, then therapeutic window is improved, but target cell killing potency may be compromised
Solution Approach 1:
The patent applies partial action by implementing moderate affinity reduction through specific amino acid substitutions that decrease CD3 binding sufficiently to lower cytokine release but maintain enough binding to preserve target cell killing. The variant CD3-Binding Domains are designed to exhibit reduced but not eliminated CD3 binding, achieving a balance between these two opposing requirements
Solution Approach 2:
The patent creates a series of variant CD3-Binding Domains with progressively different affinity levels, allowing dynamic selection of the optimal variant for specific therapeutic applications. Different amino acid substitutions create a spectrum of binding affinities that can be matched to specific disease indications and patient needs
Data Source
AI summary
The present invention is directed to DA×CD3 Binding Molecules comprising a vCD3-Binding Domain, which comprises a CDRH1 Domain, a CDRH2 Domain, a CDRH3 Domain, a CDRL1 Domain, a CDRL2 Domain, and a CDRL3 Domain, at least one of which differs in amino acid sequence from the amino acid sequence of the corresponding CDR of a rCD3-Binding Domain, wherein the DA×CD3 Binding Molecule comprising such vCD3-Binding Domain exhibits an altered affinity for CD3, relative to a DA×CD3 Binding Molecule comprising such rCD3-Binding Domain. The invention particularly concerns to such DA×CD3 Binding Molecules comprising a vCD3-Binding Domain which exhibit reduced affinity for CD3 and are capable of mediating redirected killing of target cells expressing a DA and exhibit lower levels of cytokine release relative to a DA×CD3 Binding Molecule comprising a rCD3-Binding Domain. The invention particularly concerns the use of DA×CD3 Binding Molecules comprising a vCD3-Binding Domain in the treatment of cancer and pathogen-associated diseases. The present invention is also directed to pharmaceutical compositions that comprise such molecule(s).