Fc-Integrin Fusion Polypeptides for Tumor Antibody Retention
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Solution Overview
Problem
Existing cancer therapies, particularly those involving therapeutic antibodies, face limitations due to inefficient passive diffusion and poor retention in tumor beds, as well as suppression by the tumor microenvironment, which hampers their efficacy.
Innovation Solution
Development of fusion polypeptides that combine Fc binding domains with integrin binding domains, such as those from Protein A and fibronectin type III domains, to enhance the retention and functionality of antibodies within the tumor microenvironment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic antibodies are administered to treat cancer, then anti-tumor efficacy is achieved, but retention in tumor beds is poor due to inefficient passive diffusion
Solution Approach 1:
The patent creates a composite structure by fusing the antibody (therapeutic agent) with a transmembrane protein domain that binds to extracellular matrix components. This composite fusion protein combines the anti-tumor activity of the antibody with the tissue-retention capability of the transmembrane domain, allowing the antibody to be retained in tumor beds while maintaining its therapeutic function.
Solution Approach 2:
The transmembrane protein domain acts as an intermediary between the antibody and the extracellular matrix. It mediates the anchoring of the antibody to the tumor tissue through binding to ECM components, thereby improving retention without directly altering the antibody's therapeutic mechanism.
2Reliability
If therapeutic antibodies are administered to target tumor cells, then cancer treatment is achieved, but the tumor microenvironment suppresses anti-tumor immune cells
Solution Approach 1:
The transmembrane protein domain serves as an intermediary that anchors the antibody in the tumor microenvironment, allowing sustained local concentration to overcome suppressive conditions. This mediator enables the antibody to persist in the challenging tumor environment long enough to exert its full therapeutic effect.
Solution Approach 2:
The fusion protein structure preliminarily positions the antibody within the tumor microenvironment through the transmembrane domain's anchoring function. This preliminary placement ensures the antibody is pre-positioned at the target site before immune suppression can interfere with its activity.
Data Source
AI summary
Fusion polypeptides including at least one Fc binding domain linked to at least one integrin binding domain are provided. In some embodiments, the at least one Fc binding domain is one or more Fc binding domains from Protein A, Protein G, or Protein Z and the at least one integrin binding domain comprises one or more fibronectin type III domains (for example repeats 12-14 of fibronectin type III domains and optionally the connecting segment of fibronectin). Protein complexes including the polypeptide and one or more antibodies are also provided. Methods of using the polypeptide and/or polypeptide:antibody complex are provided, including treating a subject with a tumor, inducing an immune response to a tumor, and/or targeting an antibody to a tumor cell.