Targeted 4-1BB Agonist Combination for Sustained T-Cell Activation
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Solution Overview
Problem
Current immune-based cancer therapies, including immune checkpoint inhibitors and anti-CEA/anti-CD3 bispecific antibodies, are only effective in a proportion of patients and often cause unacceptable toxicity, necessitating a combination therapy to enhance therapeutic benefit and sustain T-cell activation against cancer cells.
Innovation Solution
A combination therapy involving a T-cell activating anti-CD3 bispecific antibody, such as anti-CEA/anti-CD3, paired with a 4-1BB (CD137) agonist, specifically a 4-1BBL trimer containing antigen binding molecules, to enhance anti-tumor immunity by targeting tumor-associated antigens like FAP and avoiding Fc-mediated toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If anti-CEA/anti-CD3 bispecific antibody is used alone, then T-cell activation and tumor cell depletion occur, but T-cell activation is transient and cytokine release peaks then returns to baseline within 72 hours
Solution Approach 1:
The patent combines anti-CEA/anti-CD3 bispecific antibody with 4-1BB agonist in a combination therapy regimen. The 4-1BB agonist provides sustained co-stimulatory signaling that maintains T-cell activation beyond the transient phase induced by the bispecific antibody alone, thereby extending the duration and reliability of the immune response against tumor cells.
Solution Approach 2:
The 4-1BB agonist is administered to pre-activate and prime T cells before the transient activation by the bisspecific antibody occurs, or concurrently to ensure continuous activation. This preliminary action ensures that when the bispecific antibody induces transient activation, the T cells are already in a state ready for sustained response, preventing return to baseline.
2Reliability
If higher doses of immune-based therapies are administered to improve efficacy, then therapeutic benefit increases, but toxicity becomes unacceptable
Solution Approach 1:
The patent employs targeted 4-1BB agonists that specifically bind to tumor-associated antigens (such as FAP on cancer-associated fibroblasts or CEA on tumor cells) and recruit T cells to the tumor microenvironment. This localized activation at the tumor site achieves high efficacy while avoiding systemic toxicity that would result from high-dose non-specific immune stimulation throughout the body.
Solution Approach 2:
The 4-1BB agonist acts as an intermediary molecule that bridges the anti-CEA/anti-CD3 bisspecific antibody and T cells, providing focused co-stimulatory signals at the tumor site. This intermediary mechanism allows for effective T-cell activation with lower overall doses, reducing systemic toxicity while maintaining therapeutic benefit.
3Power
If Fc-mediated mechanisms are utilized for enhanced antibody function, then immune response is amplified, but Fc-mediated toxicity increases
Solution Approach 1:
The patent extracts or removes the Fc portion from the 4-1BB agonist molecule, using only the Fab (antigen-binding) region to provide 4-1BB agonist activity. This extraction eliminates Fc-mediated toxicity while preserving the desired immune response amplification through targeted 4-1BB receptor engagement on T cells via the antigen-binding portion.
Data Source
AI summary
The present invention relates to combination therapies employing tumor targeted anti-CEA/CD3 bispecific antibodies and/or agents blocking PD-L1/PD-1 interaction in combination with 4-1BB (CD137) agonists, in particular 4-1BBL trimer containing antigen binding molecules that also target FAP, the use of these combination therapies for the treatment of cancer and methods of using the combination therapies.