MICA Antibody Affinity Maturation for NK Cell Activation
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Solution Overview
Problem
Current cancer treatments, particularly immunotherapy using PD-1/L1 therapies, are limited in effectiveness due to tumor heterogeneity and the presence of 'cold tumors' with low gene mutation frequencies, leading to immune evasion mechanisms such as MICA/B down-regulation on tumor surfaces, which hampers NK cell recognition and activation.
Innovation Solution
Development of a MICA-targeted monoclonal antibody with high affinity, specifically binding to the α3 domain of MICA to inhibit shedding and enhance NK cell recognition, utilizing a humanized antibody with optimized CDR sequences for improved binding and therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PD-1/L1 immune checkpoint therapy is used to recover T cells' function against cancer, then T cells can recognize neo-antigens through TCR, but the therapy is ineffective to cold tumors with low gene mutation frequency and small varieties of neo-antigens
Solution Approach 1:
The patent develops a MICA-targeted antibody that can be used across multiple tumor types including cold tumors, hot tumors, and tumors resistant to PD-1/L1 therapy. The antibody targets MICA which is overexpressed on various tumor surfaces, providing universal applicability beyond the limitations of PD-1/L1 therapy that relies on neo-antigen recognition.
Solution Approach 2:
The MICA-targeted antibody acts as an intermediary that bridges NK cells and tumor cells. By binding to MICA on tumor surfaces, the antibody enables NK cell recognition and activation through NKG2D receptors, facilitating tumor killing without relying on T cell recognition of neo-antigens.
2Reliability
If tumors down-regulate MICA/B expressions through matrix metalloproteinase-mediated shedding, then tumors can escape from immune surveillance of NK cells, but this creates an immune evasion mechanism that reduces therapeutic effectiveness
Solution Approach 1:
The MICA-targeted antibody prevents MICA shedding by binding to the MICA protein on tumor surfaces before matrix metalloproteinases can cleave it. This preliminary protective action blocks the immune evasion mechanism, maintaining MICA expression and enabling sustained NK cell recognition and tumor killing.
3Reliability
If conventional cancer treatment methods such as chemotherapy and radiotherapy are used, then cancer can be treated, but the methods have disadvantages of significant side effects and easy recurrence
Solution Approach 1:
The MICA-targeted antibody therapy leverages the patient's own immune system, specifically NK cells, to recognize and kill tumor cells. This self-service approach eliminates the need for external cytotoxic agents like chemotherapy, thereby avoiding significant side effects while maintaining therapeutic efficacy through biologically specific immune-mediated tumor destruction.
4Reliability
If a MICA antibody is designed to bind to the α3 domain of MICA to inhibit shedding, then the antibody can facilitate NK cell recognition, but the antibody needs high affinity binding which requires affinity maturation
Solution Approach 1:
The patent employs affinity maturation techniques to optimize the antibody's binding parameters, specifically enhancing its affinity for the MICA α3 domain. Through iterative mutation and selection processes, the antibody's binding strength is improved, ensuring effective inhibition of MICA shedding and sustained NK cell recognition capability.
Data Source
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AI summary
Provided are an antibody or antigen-binding fragment thereof, and application thereof. The antibody or the antigen-binding fragment thereof includes: heavy chain variable region CDR1, CDR2 and CDR3 sequences as set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 or as set forth in amino acid sequences having at least 80% identity to SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3; and light chain variable region CDR1, CDR2 and CDR3 sequences as set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 or as set forth in amino acid sequences having at least 80% identity to SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. The antibody or the antigen-binding fragment thereof can bind to human and monkey MICA proteins at high affinity, thereby facilitating an effect of peripheral blood mononuclear cells (PBMC) for killing tumors.