CD47-4-1BB Chimeric Protein Complex for Selective Tumor Targeting
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Solution Overview
Problem
Current cancer therapies targeting the CD47/SIRPα pathway face challenges due to the expression of CD47 on both cancer cells and normal cells like red blood cells and platelets, leading to potential toxicities such as anemia and inflammation.
Innovation Solution
Development of protein complexes comprising a CD47-binding domain and a 4-1BB-binding domain, linked to an Fc region, which can specifically bind to CD47 on cancer cells and stimulate 4-1BB on immune cells, thereby enhancing immune response against cancer while minimizing interaction with normal cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD47/SIRPα pathway is targeted for cancer therapy, then anti-tumor immune response is enhanced, but toxicity to normal cells (anemia and inflammation) increases
Solution Approach 1:
The patent applies local quality by creating a chimeric protein where the N-terminus specifically targets CD47 on tumor cells while the C-terminus specifically engages 4-1BB on immune cells. This localized functional differentiation allows the protein to exert anti-tumor effects selectively at the tumor site while minimizing systemic toxicity to normal cells expressing CD47
Solution Approach 2:
The patent merges two distinct functional domains into a single chimeric protein molecule: the CD47-binding domain (from SIRPα) and the 4-1BB-binding domain (from 4-1BBL). This combination allows simultaneous engagement of both CD47 on tumor cells and 4-1BB on immune cells, creating a dual-mechanism therapy that enhances anti-tumor immunity while reducing off-target effects
2Productivity
If CD47/SIRPα pathway is targeted, then phagocytosis of cancer cells is promoted, but phagocytosis of red blood cells and platelets occurs causing anemia
Solution Approach 1:
The patent introduces 4-1BB engagement as an intermediary mechanism that mediates selective immune cell activation. The chimeric protein uses 4-1BB on immune cells as an intermediate to transmit the anti-tumor signal, which distinguishes tumor cells from normal red blood cells and platelets that lack 4-1BB expression, thereby preventing off-target phagocytosis
Solution Approach 2:
The chimeric protein exhibits local quality by having its CD47-binding domain selectively engage CD47 on tumor cells while its 4-1BB-binding domain selectively engages 4-1BB on immune cells. This spatial and functional differentiation ensures that phagocytosis is promoted only in the context of tumor-immune cell interactions, not in normal physiological processes involving red blood cells and platelets
Data Source
AI summary
This disclosure relates to protein complexes targeting CD47 and 4-1BB, and methods of use thereof. In one aspect, the protein complexes include one or more CD47-binding domains including all or a portion of the SIRPα extracellular regions, and one or more 4-1BB-binding domains including all or a portion of the 4-1BBL extracellular region.