OX40-Binding Antibodies With Fc Mutations for T-Cell Activation
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Solution Overview
Problem
There is a need for agonistic OX40 therapeutic antibodies that enhance antitumor immune responses, as existing antibodies may not effectively activate T cells and induce potent immune responses in certain conditions.
Innovation Solution
Development of antibodies capable of binding to human OX40 with specific CDR sequences and a mutated Fc region, such as a P329R and E345R mutation, which enhance T-cell activation and antitumor responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional agonistic OX40 antibodies are used, then T-cell activation may occur, but the antitumor immune response is insufficient
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations (P329R and E345R) in the Fc region of the antibody. These mutations alter the biochemical parameters of the antibody, specifically enhancing its ability to crosslink Fcγ receptors on immune cells, thereby increasing T-cell activation potency and antitumor immune response efficacy
Solution Approach 2:
The patent creates a composite functional structure by combining the antigen-binding region (variable domains) with the modified Fc region containing P329R and E345R mutations. This composite design integrates dual functions: specific OX40 binding capability and enhanced Fc-mediated immune activation, resulting in superior antitumor efficacy compared to conventional antibodies
2Productivity
If OX40 signaling is activated, then effector T-cell expansion occurs, but Treg proliferation may be induced under certain conditions
Solution Approach 1:
The patent applies local quality by creating spatially distinct functional zones within the antibody structure. The variable regions provide localized antigen binding to OX40 on T cells, while the modified Fc region (with P329R and E345R mutations) provides localized enhanced interaction with Fcγ receptors on effector cells. This localized functional differentiation enables selective activation of desirable immune responses while minimizing unwanted Treg proliferation
3Productivity
If antibody structure is modified to enhance Fc region activity, then T-cell activation is improved, but manufacturing complexity increases
Solution Approach 1:
The patent implements parameter changes by introducing only two specific amino acid substitutions (P329R and E345R) in the Fc region rather than extensive structural modifications. This minimal parameter change approach achieves enhanced T-cell activation while maintaining relatively simple antibody structure, thereby reducing manufacturing complexity compared to more extensively engineered antibody variants
Data Source
AI summary
The present invention relates to antibodies capable of binding to human OX40 and to variants thereof comprising a modified Fc region comprising at least one mutation that enhances the Fc-Fc interaction of the antibody and at least one mutation that reduces the Fc effector functions of the antibody. The invention further provides pharmaceutical compositions comprising the antibodies and use of the antibodies for therapeutic and diagnostic procedures, in particular in cancer therapy.