Histidine-Mutated Anti-HIV Antibodies for pH-Dependent Binding
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Solution Overview
Problem
Current anti-HIV antibodies, such as ibalizumab, face challenges with resistance from HIV variants that have lost asparagine-linked glycosylation sites in the variable region 5 of the HIV envelope, limiting their effectiveness in preventing and treating HIV infections.
Innovation Solution
Introducing histidine mutations at specific residues in the heavy and light chains of anti-HIV antibodies, such as Y53a, D58, K96, D97, N98, S26, L30, L33, Q89, Y92, and Y94, to enhance glycan modification and improve antibody activity, including the development of glycan-modified anti-CD4 monoclonal antibodies with extended half-life and increased CD4 receptor occupancy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ibalizumab binds to domain 2 of CD4 receptor to neutralize HIV, then broad neutralization activity is achieved, but resistance develops from HIV variants that lose asparagine-linked glycosylation sites in variable region 5
Solution Approach 1:
The patent introduces an N-linked glycosylation site at a specific position in the variable region of the anti-HIV antibody. This localized modification creates a new functional feature (glycan attachment) that specifically addresses the resistance mechanism by HIV variants that have lost glycosylation sites, while maintaining the antibody's overall binding function to CD4 domain 2.
Solution Approach 2:
The patent modifies the antibody structure by introducing a glycosylation site, which changes the physical-chemical parameters of the antibody molecule. This structural parameter change (addition of carbohydrate moiety) enhances the antibody's ability to bind to HIV envelope proteins that have lost their own glycosylation sites, thereby overcoming resistance.
2Reliability
If glycan modification is introduced in the variable region of anti-HIV antibody, then activity against glycosylation-deficient variants is improved, but structural complexity increases
Solution Approach 1:
Instead of modifying the entire antibody structure, the patent introduces a single N-linked glycosylation site at a specific position in the variable region. This localized modification adds minimal structural complexity while providing the desired functional improvement against glycosylation-deficient HIV variants.
3Reliability
If multiple histidine mutations are introduced at specific residues, then pH-dependent binding activity is enhanced, but manufacturing complexity increases
Solution Approach 1:
The patent introduces multiple histidine mutations at specific residues (such as Y53a, D58, K96, D97, N98 in the heavy chain and S26, L30, L33, Q89, Y92, Y94 in the light chain) to create pH-dependent binding activity. These point mutations are relatively simple to implement through standard molecular biology techniques, and the histidine side chains provide pH-sensitive properties that enhance binding at physiological pH while allowing for easier dissociation at lower pH for recycling.
Data Source
AI summary
The disclosure is directed to a histidine-mutated anti-HIV antibody having one or more mutations at the residue Y53a, D58, K96, D97, N98, or T100a in the heavy chain of ibalizumab, and at the residue S26, L30, L33, Q89, Y92, S93 or Y94 in the light chain of ibalizumab. In addition, the disclosure also is directed to two histidine mutated variants with two mutations, one with mutations at the residues Y53a and Y94, and the other with mutations at the residues D58 and L30 in the heavy and light chains of ibalizumab, respectively.