Multi-Specific Binding Proteins With Albumin-Mediated Half-Life Extension
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Solution Overview
Problem
Existing bispecific T-cell engager (BiTE®) constructs, such as blinatumomab and solitomab, have short in vivo half-lives, requiring continuous intravenous infusions and are species-specific, leading to inconvenient treatment and potential side effects, while improved constructs lack adequate therapeutic efficacy and favorable pharmacokinetic properties.
Innovation Solution
Development of multi-specific binding proteins with domains that bind CD19, CD3, and serum albumin, linked in specific arrangements for enhanced therapeutic efficacy and prolonged in vivo half-life, including single-chain variable fragments (scFv) and single-domain antibodies (sdAb) with optimized binding affinities and temperatures, and optionally without an Fc region for improved pharmacokinetics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If BiTE® constructs are used to engage T cells and target cells, then immune stimulation and cytolytic potential are activated, but in vivo half-life is short requiring continuous intravenous infusions
Solution Approach 1:
The patent introduces serum albumin binding domains as an intermediary mechanism to extend the circulation half-life of the bispecific T-cell engager. By adding domains that bind to serum albumin (such as human serum albumin binding domains), the construct utilizes the long circulation half-life of albumin to prolong its own presence in the bloodstream, thereby reducing the frequency of intravenous infusions required for therapeutic effect.
2Reliability
If species-specific binding domains are used in BiTE® constructs, then binding affinity is optimized for specific species, but cross-species applicability is limited and side effects increase
Solution Approach 1:
The patent employs binding domains with cross-species reactivity, particularly for CD3 binding. The CD3 binding domain is designed to recognize conserved epitopes across different species (human, non-human primates, and other mammals), making the construct universally applicable across species while maintaining reliable binding. This universality reduces the need for species-specific optimization and minimizes immunogenicity and side effects associated with species-mismatched proteins.
3Reliability
If continuous intravenous infusions are administered to maintain therapeutic levels, then therapeutic efficacy is maintained, but treatment complexity and cost increase
Solution Approach 1:
The patent achieves continuous therapeutic action through prolonged in vivo persistence of the modified BiTE® construct. By engineering the construct to bind serum albumin, it remains in circulation for extended periods, maintaining therapeutic levels without requiring continuous external administration. This transforms the treatment from a continuous infusion protocol to a discrete dosing regimen, thereby reducing treatment complexity while preserving efficacy.
Data Source
AI summary
The invention relates to multi-specific binding proteins that bind CD19, CD3, and serum albumin. The invention also relates to pharmaceutical compositions comprising these multi-specific binding proteins, expression vectors and host cells for making these multi-specific binding proteins, and methods of use of these multi-specific binding proteins in treating hematologic cancers.