FAP-Targeted Antigen-Binding IFNG Fusions for Tumor Activation
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Solution Overview
Problem
Existing immunotherapy treatments for cancer face challenges due to intrinsic or adaptive resistance mechanisms, particularly in patients with a non-inflamed immune phenotype, and interferon gamma (IFNG) therapies suffer from dose-limiting toxicity, sink effects, and undesirable side effects, limiting their effectiveness in enhancing immune cell infiltration in tumors.
Innovation Solution
Development of tumor-targeting, masked IFNG variants conjugated to antibodies that bind to Fibroblast Activation Protein (FAP), specifically terminating with the C-terminal amino acid sequence KRKRP, to deliver active IFNG directly to the tumor site, activating T cells and enhancing immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If interferon gamma (IFNG) is used as a cancer therapy, then immune cell infiltration and anti-tumor immune response are enhanced, but dose-limiting toxicity and undesirable side effects occur
Solution Approach 1:
The IFNG variant is engineered with a specific C-terminal amino acid sequence KRKRP that enables selective accumulation and activation at the tumor site rather than systemic distribution. This local quality enhancement allows high IFNG activity where needed while minimizing systemic toxicity
Solution Approach 2:
The patent uses an antibody fragment as an intermediary carrier to deliver the IFNG variant specifically to tumor cells expressing target antigens. This intermediary approach ensures targeted delivery, enhancing anti-tumor response while reducing off-target side effects
2Quantity of substance
If IFNG is administered systemically, then immune cell recruitment is increased, but sink effects reduce its effectiveness
Solution Approach 1:
The IFNG variant with C-terminal KRKRP sequence exhibits localized action at the tumor microenvironment, concentrating immune cell recruitment effects where needed while avoiding systemic sink effects that would otherwise reduce therapeutic effectiveness
3Reliability
If new therapies are developed to enhance immunogenicity, then immune cell infiltration is improved, but treatment complexity increases
Solution Approach 1:
The invention creates a composite therapeutic molecule combining an antibody fragment with an IFNG variant through genetic fusion. This composite structure integrates targeting and immunomodulatory functions into a single agent, enhancing immune cell infiltration while maintaining relatively simple administration protocols
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The approach enables targeted activation of T cells in the tumor microenvironment, overcoming dose limitations and improving immune cell infiltration, particularly in immune desert tumors, thereby enhancing anti-tumor immune responses.
Implementation Method 1
Binding of IFNG to its receptors induces recruitment and activation of the Janus kinases, JAK1 and JAK2
Implementation Method 2
After phosphorylation, STAT1 translocates to the nucleus where it binds specific promoters and modulates the transcription of IFNG-regulated genes
Data Source
AI summary
The invention relates to new antigen binding molecules comprising (i) an antibody that specifically binds to a tumor associated antigen and (ii) an interferon gamma (IFNG) variant polypeptide that terminates with the C-terminal amino acid sequence KRKRP (SEQ ID NO:1), to the new IFNG variant polypeptides included therein, to methods of producing these molecules and to methods of using the same.