BCMA Trispecific Protein With CD3 Bridging and Half-Life Extension
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Solution Overview
Problem
Current cancer therapies lack effective and non-toxic systemic treatments that can selectively target and destroy cancer cells while sparing healthy cells and tissues.
Innovation Solution
Development of a BCMA binding trispecific protein comprising domains that specifically bind to human CD3, a half-life extension domain, and BCMA, linked by specific sequences and linkers, to enhance targeting and persistence in the body.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer therapies are used, then tumor cells can be destroyed, but healthy cells and tissues are damaged causing significant physical debilitations
Solution Approach 1:
The therapeutic agent is divided into multiple functional domains: a tumor-targeting domain (anti-BCMA), a T cell engagement domain (anti-CD3), and a half-life extension domain (albumin-binding). This segmentation allows each domain to perform its specific function independently while working together to achieve selective tumor cell destruction through antibody-dependent cellular cytotoxicity (ADCC), reducing damage to healthy cells
Solution Approach 2:
The patent introduces immune effector cells (specifically T cells expressing CD3) as intermediaries between the therapeutic protein and tumor cells. The trispecific protein acts as a bridge that simultaneously binds to BCMA on tumor cells and CD3 on T cells, enabling selective recruitment and activation of immune cells against tumor targets while sparing healthy tissues
2Duration of action of moving object
If short-lived therapeutic proteins are used, then rapid clearance occurs, but the duration of therapeutic action is insufficient for effective cancer treatment
Solution Approach 1:
The patent employs albumin as an intermediary carrier protein to extend the half-life of the therapeutic agent. The albumin-binding domain (ABD) facilitates binding to endogenous albumin, which protects the therapeutic protein from rapid renal clearance and proteolytic degradation, thereby extending circulation time and reducing administration frequency
Solution Approach 2:
The patent modifies the pharmacokinetic parameters of the therapeutic protein by incorporating a half-life extension domain that binds to albumin. This changes the elimination half-life from hours to days, allowing for less frequent dosing while maintaining therapeutic efficacy
3Adaptability or versatility
If non-specific systemic therapies are used, then broad coverage is achieved, but toxicity increases causing patient anxieties and physical debilitations
Solution Approach 1:
The therapeutic protein exhibits local quality by displaying different binding properties at different locations: high affinity for BCMA at the tumor site, high affinity for CD3 at the T cell interface, and high affinity for albumin in the circulation. This spatially differentiated binding ensures selective action at the tumor target while maintaining stability in circulation, reducing systemic toxicity
Data Source
AI summary
Provided herein are B cell maturation agent (BCMA) targeting trispecific proteins comprising a domain binding to CD3, a half-life extension domain, and a domain binding to BCMA. Also provided are pharmaceutical compositions thereof, as well as nucleic acids, recombinant expression vectors and host cells for making such BCMA targeting trispecific proteins. Also disclosed are methods of using the disclosed BCMA targeting trispecific proteins in the prevention, and/or treatment diseases, conditions and disorders.