Soluble Monospecific Tetrameric Antibody Complexes for T Cell Activation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for T cell and NK cell activation and expansion often require immobilized antibodies, accessory cells, and exogenous growth factors, leading to inefficiencies and potential activation-induced cell death, and existing soluble bispecific tetrameric antibody complexes are not fully soluble and may not demonstrate optimal activation.
Innovation Solution
The use of soluble monospecific tetrameric antibody complexes that bind to the same antigen on T or NK cells, optionally with combinations of CD3, CD28, CD2, CD335, and CD2, to activate and expand these cells without the need for immobilized surfaces or additional growth factors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If soluble bisspecific tetrameric antibody complexes are used for T cell activation, then T cell activation and expansion can be achieved, but the complexes are not fully soluble and may not demonstrate optimal activation
Solution Approach 1:
The invention divides the bispecific tetrameric complex into separate monosspecific complexes. Instead of using one complex that binds both CD3 and CD28, the invention uses separate complexes: one that binds CD3 and another that binds CD28. This segmentation resolves the solubility issue while maintaining activation efficacy.
Solution Approach 2:
The invention introduces Fc fragment crystallizable (Fc) protein as an intermediary to crosslink the monospecific antibody complexes. The Fc protein binds to the Fc regions of the antibody complexes, forming a stable crosslinked structure that enhances solubility and activation efficiency without requiring immobilization on solid surfaces.
2Reliability
If immobilized anti-CD3 antibodies are used on solid phase surfaces, then T cell activation signal is provided, but accessory cells and exogenous growth factors are required for full activation and expansion
Solution Approach 1:
The invention merges the primary activation signal (anti-CD3) and the costimulatory signal (anti-CD28) into a single soluble complex system. By combining these signals in one crosslinked complex structure, the invention eliminates the need for separate accessory cells and exogenous growth factors, reducing system complexity while maintaining full activation capability.
Solution Approach 2:
The soluble crosslinked antibody complexes provide self-service by delivering both activation and costimulatory signals simultaneously without requiring external support systems. The complexes autonomously bind to T cell receptors and costimulatory molecules, eliminating dependence on accessory cells for signal delivery.
3Reliability
If immobilized antibodies are used for T cell activation, then activation is achieved, but activation-induced cell death increases
Solution Approach 1:
The invention changes the physical state parameter from immobilized to soluble, and modifies the valency parameter by using crosslinked monospecific complexes. This parameter change allows the antibody complexes to remain in solution and provide gentler, more controlled activation signals that reduce activation-induced cell death while maintaining activation efficacy.
Data Source
AI summary
This disclosure provides compositions and methods for the activation and expansion of human T cells or NK cells using soluble monospecific antibody complexes.