Anti-PSGL-1 Antibodies Blocking Selectin and Chemokine Binding
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Solution Overview
Problem
Current treatments for inflammatory and thrombotic conditions involving PSGL-1 selectin interactions are limited in efficacy, as they often require blocking multiple selectins and chemokines simultaneously, and existing antibodies may activate complement or bind Fc receptors, leading to unwanted immune responses.
Innovation Solution
Development of purified antibodies, including chimeric and humanized forms, that specifically bind to PSGL-1 with high affinity, blocking both P- and L-selectin and chemokine binding without activating complement or binding to Fc receptors, thereby inhibiting leukocyte and lymphocyte adhesion and chemotaxis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing antibodies are used to block selectin interactions, then some inflammatory response inhibition is achieved, but they activate complement or bind Fc receptors causing unwanted immune responses
Solution Approach 1:
The patent applies parameter changes by modifying the antibody constant region to alter its effector function properties. Specifically, the antibody is engineered to have reduced or abolished binding to Fc receptors and complement protein C1q, while maintaining high affinity binding to PSGL-1. This changes the immunological parameters of the antibody from activating immune responses to minimizing them, thereby resolving the contradiction between therapeutic efficacy and unwanted immune activation.
2Reliability
If multiple selectins and chemokines are blocked simultaneously to improve efficacy, then treatment effectiveness increases, but the complexity of the therapeutic approach increases
Solution Approach 1:
The patent applies universality by designing a single antibody that performs multiple functions: it blocks both P-selectin and L-selectin interactions with PSGL-1, and simultaneously inhibits chemokine binding to PSGL-1. This multi-functional antibody consolidates what would otherwise require multiple separate therapeutic agents into one treatment, thereby maintaining high effectiveness while reducing overall therapeutic complexity.
3Reliability
If high affinity binding to PSGL-1 is achieved to improve adhesion inhibition, then selectin blocking is enhanced, but the risk of off-target effects may increase
Solution Approach 1:
The patent applies local quality by ensuring the antibody has high binding affinity specifically for the PSGL-1 epitope while having reduced or no binding to other targets. The antibody is engineered with specific variable regions that confer high affinity for PSGL-1, while the modified constant region ensures selective interaction only with the intended target, minimizing off-target effects despite high local binding strength at the PSGL-1 site.
Data Source
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Figure 3A~3B
AI summary
The present invention is directed to antibodies and binding fragments thereof, which bind with high affinity and specificity to human P-selectin glycoprotein ligand 1 (PSGL-1) and which block both selectin and chemokine binding to PSGL-1 expressed on leukocytes, lymphocytes and endothelial cells and thus which inhibit migration and/or rolling of these cells and to methods for screening for such antibodies and binding fragments thereof and to methods of therapeutic use thereof.