Variant CD86 Immunomodulatory Proteins for Selective CD28 Binding
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Solution Overview
Problem
Current therapeutics for modulating immune responses at the immunological synapse are inadequate, necessitating improved immunomodulatory proteins that can enhance or alter binding affinities to key proteins like CD28 and CTLA-4 for effective immune modulation.
Innovation Solution
Development of variant CD86 polypeptides with specific amino acid modifications, particularly at positions 25 and 90, that exhibit increased affinity for CD28 and decreased or similar affinity for CTLA-4, along with the use of multimerization domains and linkers to form immunomodulatory proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutics are used to modulate immune response at the immunological synapse, then immune modulation is achieved, but the binding affinity for key proteins like CD28 and CTLA-4 is insufficient
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid residues at specific positions (13, 18, 25, 28, 33, 38, 39, 40, 43, 45, 52, 53, 60, 68, 71, 77, 79, 80, 82, 86, 88, 89, 90, 92, 93, 97, 102, 104, 113, 114, 123, 128, 129, 132, 133, 137, 141, 143, 144, 148, 153, 154, 158, 170, 172, 175, 178, 180, 181, 183, 185, 192, 193, 196, 197, 198, 205, 206, 207, 212, 215, 216, 222, 223, or 224) in the CD86 polypeptide sequence to optimize binding affinity for CD28 and CTLA-4 proteins
Solution Approach 2:
The patent applies local quality by making specific amino acid substitutions at particular positions within the CD86 sequence, such as Q25L, H90Y, H90L, and combinations thereof, to create localized changes that enhance binding affinity for CD28 while differentially modulating interaction with CTLA-4
2Reliability
If amino acid modifications are made to increase affinity for CD28, then binding affinity for CD28 is improved, but affinity for CTLA-4 may increase or remain unchanged
Solution Approach 1:
The patent uses parameter changes by testing multiple amino acid substitutions at key positions (particularly 25, 90, and combinations) to achieve differential binding profiles where affinity for CD28 is enhanced while affinity for CTLA-4 is reduced or maintained at wild-type levels
Solution Approach 2:
The patent applies local quality by making targeted amino acid changes at specific positions that differentially affect binding to CD28 versus CTLA-4, creating immunomodulatory proteins with customized binding characteristics for each protein partner
Data Source
AI summary
Provided herein are variant CD86 polypeptides, immunomodulatory proteins comprising variant CD86 polypeptides, and nucleic acids encoding such proteins. The immunomodulatory proteins provide therapeutic utility for a variety of immunological and oncological conditions. Compositions and methods for making and using such proteins are provided.