Chimeric Polypeptide Assembly with Cleavable Release Segments
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Solution Overview
Problem
Current cancer therapeutics, such as cytotoxic drugs and bispecific antibodies, often cause severe side effects like 'cytokine storm' and require frequent dosing due to short half-life, limiting their therapeutic window and increasing toxicity to healthy tissues.
Innovation Solution
A chimeric polypeptide assembly with a cleavable design, comprising binding domains specific to tumor cells and effector cells, a peptidyl release segment for protease-mediated activation, and a bulking moiety for enhanced stability and targeted delivery, allowing for selective cytotoxic activity and reduced toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bispecific antibodies are used to redirect effector cells to tumor targets, then targeted cytotoxic activity is improved, but the therapeutic composition requires frequent dosing due to very short half-life
Solution Approach 1:
The patent creates a composite therapeutic composition by conjugating bispecific antibody fragments (affibodies) with a long-circulating carrier protein (albumin). This composite structure combines the targeted cytotoxic activity of the affibody with the extended half-life of albumin, achieving both reliability and duration without requiring frequent dosing
2Reliability
If cytotoxic drugs are used to kill tumor cells, then therapeutic benefit is improved, but severe damage to normal tissues occurs resulting in unacceptable side effects
Solution Approach 1:
The patent implements local quality by designing the affibody to specifically bind tumor-associated antigens (such as EGFR, HER2, or PSMA) while the albumin carrier provides long circulation. The cytotoxic effect is localized to tumor cells through the specific binding of the affibody, minimizing damage to normal tissues and reducing systemic toxicity
3Reliability
If BiTE compositions are used to recruit and activate T-cells at tumor sites, then cytotoxic activity is improved, but patients experience serious side effects referred to as cytokine storm
Solution Approach 1:
The patent changes the pharmacokinetic parameters of the therapeutic by conjugating the affibody with albumin, extending the half-life from minutes to days. This parameter change allows for sustained, lower-dose therapy rather than high-dose continuous infusion, reducing the intensity of T-cell activation and thereby minimizing cytokine release syndrome while maintaining cytotoxic efficacy
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
The chimeric polypeptide assembly achieves enhanced terminal half-life, reduced toxicity, and increased selectivity, enabling effective tumor targeting with reduced side effects and less frequent dosing, as the cleavage mechanism activates the therapeutic agent only at the tumor site.
Implementation Method 1
said second portion comprises a peptidyl release segment (RS) capable of being cleaved by one or more mammalian proteases; and said third portion comprises a bulking moiety; wherein said bulking moiety is capable of being released from said first portion by action of said mammalian protease on said second portion
Data Source
AI summary
The present invention relates to bispecific chimeric polypeptide assembly compositions comprising bulking moieties linked to binding domains by cleavable release segments that, when cleaved are capable of concurrently binding effector T cells with targeted tumor or cancer cells and effecting cytolysis of the tumor cells or cancer cells. The invention also provides compositions and methods of making and using the cleavable chimeric polypeptide assembly compositions.