CD3-CD47 Bispecific BiTE with Modified Fc for Prolonged Circulation
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Solution Overview
Problem
Current bispecific T cell engagers, such as Blinatumomab, have a short half-life and require continuous intravenous infusion, leading to adverse events like infection and limited application in solid tumors due to their short half-life and potent cytokine storm mechanism, while anti-CD47 antibodies cause anemia, lymphopenia, and thrombocytopenia due to Fc component-induced ADCP, reducing therapeutic efficacy.
Innovation Solution
Development of a novel anti-CD3Xanti-CD47 BiTE molecule with a non-immunogenic polymer and modified Fc region to abolish effector functions, allowing site-specific conjugation and prolonged circulation, reducing adverse effects and enhancing therapeutic window.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If Blinatumomab is used to activate T cells against tumor cells, then antitumor efficacy is improved, but half-life is shortened requiring continuous infusion
Solution Approach 1:
The patent applies parameter changes by modifying the Fc region of the bispecific antibody to alter its pharmacokinetic properties. Specifically, the Fc region is engineered to have extended half-life characteristics while maintaining the bispecific binding capability to CD3 and CD47, thereby resolving the contradiction between efficacy and duration of action
Solution Approach 2:
The patent uses composite material principles by creating a chimeric Fc region that combines features of different antibody isotypes (e.g., IgG1 and IgG2) to achieve both extended half-life and appropriate effector function. This composite Fc region integrates the advantages of different parental antibodies to solve the half-life limitation
2Reliability
If Blinatumomab is administered continuously for 4 weeks, then minimal blood level is maintained, but patient burden increases and infection risk increases
Solution Approach 1:
The patent changes the pharmacokinetic parameters of the bisspecific antibody by modifying the Fc region, resulting in extended half-life that allows for less frequent administration. This reduces the cumulative infection risk while maintaining reliable blood levels through reduced dosing frequency rather than continuous infusion
3Productivity
If anti-CD47 antibody is used to block innate immune checkpoint, then therapeutic efficacy is improved, but anemia and lymphopenia occur due to Fc component-induced ADCP
Solution Approach 1:
The patent extracts and removes the harmful Fc component from the anti-CD47 antibody construct, using only the Fab fragment binding to CD47 without the Fc-mediated ADCP activity. This extraction eliminates the cause of anemia and lymphopenia while preserving the therapeutic efficacy of CD47 blocking
Solution Approach 2:
The patent segments the antibody molecule into functional components, separating the CD47-binding Fab fragment from the Fc effector component. This segmentation allows the CD47-blocking function to be maintained while the harmful Fc-mediated cytotoxicity is eliminated, addressing the contradiction between efficacy and harmful effects
4Object-affected harmful factors
If Fc region is modified to abolish effector functions, then adverse effects are reduced, but binding affinity may be affected
Solution Approach 1:
The patent segments the antibody into Fab and Fc components, modifying only the Fc region to abolish effector functions while leaving the Fab binding regions intact. This segmentation allows independent optimization of binding affinity (in the Fab portion) and safety (in the Fc portion), resolving the contradiction between harmful effects and binding affinity
Solution Approach 2:
The patent applies local quality by making different parts of the antibody molecule have different properties: the Fab regions maintain high binding affinity for CD3 and CD47, while the Fc region is modified to have reduced or abolished effector functions. This localized differentiation allows simultaneous optimization of both binding and safety parameters
Data Source
AI summary
Provided are bispecific molecules and, in particular, long acting bispecific T cell engagers targeting CD3 and CD47 with improved efficacy, toxic profile and therapeutic window, and methods of making and using such long acting bispecific binding molecules.