CH3 Domain Variant Pair for Bispecific Antibody Heterodimer Formation
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Solution Overview
Problem
Current bispecific antibodies face challenges in enhancing their bispecificity, necessitating improvements in CH3 domain engineering to optimize heterodimer formation and minimize mispairing.
Innovation Solution
A heterodimer is formed by a first and second heavy chain CH3 domain with specific amino acid substitutions at positions such as Q347, E356, D399, K360, K370, K439, and K409, promoting favorable steric effects for heterodimer formation and unfavorable for homodimer formation, thereby increasing the yield of heterodimers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional knob-into-hole (KiH) technology is used to produce heterodimers, then approximately 80% heterodimer yield is achieved, but bisspecificity enhancement is insufficient
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions at defined positions in the CH3 domain (e.g., Q347, E356, E357, D399, K360, K370, K439, K409) to enhance heterodimer formation. These substitutions modify the physical-chemical parameters of the CH3 domain interface, creating favorable steric effects that improve both heterodimer yield and bisspecificity beyond conventional KiH technology
Solution Approach 2:
The patent applies local quality by making targeted amino acid substitutions at specific positions within the CH3 domain rather than global modifications. The substitutions are localized to the CH3 domain interface (positions Q347, E356, E357, D399, K360, K370, K439, K409), creating localized structural changes that promote heterodimer formation while maintaining overall antibody structure and function
2Reliability
If multiple amino acid substitutions are introduced in CH3 domain to enhance bisspecificity, then heterodimer formation is improved, but risk of mispairing increases
Solution Approach 1:
The patent applies asymmetry by introducing different amino acid substitutions at corresponding positions in the two CH3 domains. For example, one CH3 domain may have Q347K substitution while the other has K360Q substitution, creating asymmetric interactions that favor heterodimer formation over homodimer formation. This asymmetric design reduces mispairing by making heterodimer interface more favorable than homodimer interface
Solution Approach 2:
The patent uses the CH3 domain itself as an intermediary element that mediates between the two antibody arms. By engineering specific amino acid substitutions in the CH3 domain, the patent creates an intermediate structural platform that facilitates controlled heterodimer formation while preventing mispairing, acting as a mediator between the variable regions and the Fc region
Data Source
Figure 1~2
Figure 3
Figure 4(A)~4(D)
AI summary
The present invention relates to a heterodimer comprising a CH3 domain variant pair or a bispecific antibody comprising same and, more specifically, to a heterodimer to which a CH3 domain variant pair substituted with an amino acid at a specific position is applied, or a bispecific antibody comprising same.