SIRPα-Fc Fusion Gene Therapy for Localized CD47 Blockade
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Solution Overview
Problem
Current treatments for metastatic solid tumors are ineffective due to tumor-associated macrophages (TAMs) promoting tumor growth by expressing high levels of CD47, which evades phagocytosis, and systemic administration of CD47-blocking therapies poses safety concerns.
Innovation Solution
Gene therapy that delivers a polynucleotide encoding a secretable SIRPα-Fc fusion protein to tumor cells, allowing local production and secretion of SIRPα-Fc, which binds to CD47 and redirects TAMs to tumor cells, thereby inhibiting tumor growth.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic administration of CD47-blocking therapy is used, then antitumor activity is improved, but safety concerns increase
Solution Approach 1:
The patent applies local quality by enabling localized production of the SIRPα-Fc fusion protein at the tumor site through gene therapy delivery. The polynucleotide is delivered to tumor cells or tumor microenvironment cells, which then produce and secrete the fusion protein locally, creating high concentration at the target site while minimizing systemic exposure and side effects
Solution Approach 2:
The patent uses a polynucleotide as an intermediary to deliver the therapeutic gene to tumor cells or tumor microenvironment cells. This intermediary approach allows the therapeutic protein to be produced in situ rather than administered systemically, resolving the contradiction between efficacy and safety
2Ease of operation
If soluble SIRPα ectodomain is used alone, then CD47 binding is achieved, but antitumor activity is insufficient
Solution Approach 1:
The patent merges the CD47-binding SIRPα ectodomain with the Fc region of IgG4 to create a fusion protein. This combination provides both CD47 blocking capability and Fc-mediated macrophage activation through FcγRI binding, thereby achieving both easy CD47 blocking and potent antitumor activity
Solution Approach 2:
The SIRPα-Fc fusion protein performs multiple functions: it blocks CD47 to remove the 'don't eat me' signal, and simultaneously activates macrophages through FcγRI binding. This multi-functionality resolves the insufficiency of using soluble SIRPα ectodomain alone
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
This approach effectively targets and kills tumor cells by redirecting TAMs, reducing tumor growth and tumorigenicity, while minimizing systemic side effects through localized production and action.
Implementation Method 1
While macrophages normally phagocytose and kill tumor cells, TAMs promote tumor growth. Tumor cells express high levels of CD47 that binds to signal-regulatory protein alpha (SIRPα), an inhibitory receptor on macrophages, allowing tumor cells to evade phagocytosis.
Implementation Method 2
The Fc portion of IgG4 was chosen because it does not fix complement but binds hFcγRI expressed on macrophages with high affinity.
Data Source
AI summary
Embodiments of the disclosure concern treatment of cancer utilizing methods and compositions that block CD47 such that tumor associated macrophages (TAMs) are not inhibited by CD47 and are able to phagocytose and kill tumor cells. In specific embodiments, the compositions and their use concern fusions of an entity that binds CD47 and an entity that binds cells having FC receptors, such as the FC receptor on TAMs. Certain embodiments concern gene therapy that produces a fusion of the ectodomain of SIRPa and the constant region of IgG4 at a localized tumor or tumor microenvironment, for example. In specific cases, gene transfer is utilized to deliver SIRPa fusion genes into a tumor and/or tumor microenvironment so that the molecules can be expressed locally to increase efficacy (given that the expression of the molecules will be highest at tumor sites) and decrease potential toxicities.