Bispecific Antibody Design for Pertussis Toxin Neutralization
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Solution Overview
Problem
Current antibody therapies for pertussis infections, such as those caused by Bordetella pertussis, are complex and costly to manufacture, with limited efficacy and increased side effects due to the need for multiple antibodies and strict regulatory approvals.
Innovation Solution
Development of bispecific antibodies that bind to the pertussis toxin protein with high affinity, incorporating humanized 1B7 and 11E6 antibody components and modifications to enhance stability and specificity, allowing for reduced dosages and extended in vivo half-lives, and inclusion of IgG constant region mutations for increased FcRn binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody cocktails comprising different antibodies that bind the pertussis toxin protein are used, then the coverage of different epitopes is improved, but the manufacturing complexity and cost increase
Solution Approach 1:
The patent combines two separate monoclonal antibodies (1B7 and 11E6) into a single bispecific antibody molecule. This merging approach maintains the ability to bind multiple epitopes on the pertussis toxin (improving efficacy) while eliminating the need for separate production, mixing, and quality control of multiple antibodies (reducing manufacturing complexity). The bispecific antibody is produced as a single molecular entity through recombinant DNA technology.
Solution Approach 2:
The bispecific antibody serves multiple functions simultaneously: it binds to two different epitopes on the pertussis toxin (1B7 epitope and 11E6 epitope), provides neutralization activity, and enables reduced dosing. This multi-functionality is achieved by engineering the antibody to contain both 1B7 and 11E6 variable regions within a single IgG molecule, allowing one antibody preparation to deliver the combined benefits of multiple antibodies.
2Ease of manufacture
If monoclonal antibody preparations are used, then the manufacturing process is simplified, but the efficacy is limited due to binding only a single epitope
Solution Approach 1:
The patent merges the epitope-specific binding capabilities of two monoclonal antibodies (1B7 and 11E6) into a single bispecific antibody molecule. This allows the preparation to maintain manufacturing simplicity (single antibody production) while achieving enhanced efficacy through dual epitope binding, effectively combining the advantages of both monoclonal and polyclonal approaches.
Solution Approach 2:
The bispecific antibody can be formulated as composite preparations combining the bispecific antibody with other therapeutic agents. This composite approach allows for simplified manufacturing of each component while achieving synergistic efficacy through the combination of multiple mechanisms of action, including neutralization by the bispecific antibody and additional therapeutic effects from co-administered agents.
3Stability of the object's composition
If standard IgG constant regions are used, then the antibody structure is stable, but the in vivo half-life is limited
Solution Approach 1:
The patent modifies the IgG constant region by introducing specific amino acid substitutions (M252Y/S254T/T256E and H433K/N434F/Y436H) that change the binding parameters of the Fc region to the neonatal Fc receptor (FcRn). These parameter changes increase the affinity for FcRn, thereby extending the in vivo half-life of the antibody while maintaining the overall structural stability of the IgG molecule.
Data Source
AI summary
The present invention relates, in part, to bispecific antibodies that bind the pertussis toxin protein. The present invention further relates to the use of the bispecific antibodies for the prevention and treatment of Bordetella pertussis infections.