Chimeric Antibody Carrier Stability and Pharmacokinetics
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Solution Overview
Problem
Current carrier antibodies for pharmacologically active moieties face challenges in achieving uniform expression, stability, and pharmacokinetic properties, including resistance to degradation and oxidation, while maintaining non-aggregation and avoiding cross-reactivity with human antigens.
Innovation Solution
Development of an isolated antigen binding protein comprising specific immunoglobulin heavy and light chain variable regions, with optional conjugation of pharmacologically active polypeptides, recombinantly produced and structured to enhance stability and pharmacokinetics, such as through insertion within the Fc domain of the immunoglobulin heavy chain or conjugation at the N- or C-terminus of the immunoglobulin chains.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional carrier antibodies are used to conjugate pharmacologically active moieties, then the pharmacologically active moiety can be protected from degradation, but the carrier antibody may aggregate or cross-react with human antigens, and expression uniformity is poor
Solution Approach 1:
The patent applies local quality by creating a chimeric antibody with distinct regions: the variable regions are derived from human sequences to ensure non-cross-reactivity with human antigens, while the constant regions are from non-human species to provide carrier functions. This localized differentiation of species origin in different antibody regions resolves the contradiction between stability and harmful factors.
Solution Approach 2:
The chimeric antibody functions as a composite material combining human and non-human protein components. The human variable regions provide antigen binding specificity without cross-reactivity, while the non-human constant regions provide carrier functions. This composite structure enables simultaneous achievement of stability and elimination of harmful factors.
2Manufacturing precision
If the immunoglobulin is engineered with specific variable regions to improve specificity, then cross-reactivity with human antigens is reduced, but manufacturing uniformity and expression efficiency may be compromised
Solution Approach 1:
The antibody is segmented into functionally distinct regions with different species origins: human variable regions for specificity and non-human constant regions for carrier functions. This segmentation allows each region to be optimized independently, maintaining high expression uniformity through the non-human constant regions while achieving high specificity through human variable regions.
3Duration of action of moving object
If the carrier antibody is designed to extend serum half-life, then pharmacokinetic properties are improved, but the antibody may be more susceptible to photodegradation and oxidation
Solution Approach 1:
The patent converts the potential harm of using non-human constant regions (which might be more susceptible to degradation) into a benefit by carefully selecting non-human species with antibody constant regions that inherently possess resistance to photodegradation and oxidation. The carrier function extends serum half-life while the specific non-human constant region sequences provide protection against degradation.
Data Source
Figure 1A~1D
Figure 1E~1G
Figure 1H~1I
AI summary
Disclosed is an isolated antigen binding protein, such as but not limited to, an antibody or antibody fragment. Also disclosed are pharmaceutical compositions and medicaments comprising the antigen binding protein, isolated nucleic acid encoding it, vectors, host cells, and hybridomas useful in methods of making it. In some embodiments the antigen binding protein comprises one to twenty-four pharmacologically active chemical moieties conjugated thereto, such as a pharmacologically active polypeptide.