Bispecific TCR-scFv Formulation for Low-Concentration Stability
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Solution Overview
Problem
The formulation of bispecific proteins comprising a soluble T cell receptor (TCR) and an scFv is challenging due to their inherent instability, particularly at low concentrations and elevated temperatures, leading to aggregation and degradation, which existing antibody formulation technologies cannot adequately address.
Innovation Solution
A pharmaceutical formulation comprising a therapeutically effective amount of a bispecific protein with a specific ratio of surfactant to protein (0.75:1 to 1.5:1), using polysorbate as the surfactant, a disaccharide as the stabilizer, and a polyol as the bulking agent, with a stabilizer to bulking agent ratio greater than 1:1, to maintain stability during long-term storage and at elevated temperatures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Power
If low protein concentration is used in formulation, then the therapeutic potency is improved, but the protein stability deteriorates due to aggregation and absorption loss
Solution Approach 1:
The patent introduces specific excipients (surfactants, stabilizers, buffers) as intermediary substances that mediate between the low protein concentration requirement and the need to prevent aggregation. These excipients create a protective environment that allows the protein to remain stable at low concentrations without sacrificing therapeutic potency.
Solution Approach 2:
The patent systematically changes formulation parameters including pH, ionic strength, temperature, and excipient concentrations to optimize both low protein concentration stability and therapeutic activity. By adjusting these parameters, the formulation maintains protein stability while preserving the enhanced potency at low concentrations.
2Ease of operation
If elevated temperature storage is used, then the ease of transport and storage is improved, but the protein stability deteriorates due to aggregation and degradation
Solution Approach 1:
The patent incorporates stabilizing excipients and buffers in advance that cushion against the destabilizing effects of elevated temperature storage. These pre-added substances create a protective matrix that prevents aggregation and degradation even when stored at higher temperatures, enabling convenient transport and storage conditions.
3Volume of stationary object
If high protein concentration is used in formulation, then the volume of pharmaceutical product is reduced, but the protein stability is improved for antibodies but not for TCR bispecific proteins
Solution Approach 1:
The patent changes the formulation parameters specifically for TCR bisspecific proteins to accommodate low concentration stability, unlike antibody formulations that can tolerate high concentrations. By optimizing pH, ionic strength, and excipient ratios, the formulation achieves stability at low concentrations, allowing for reduced dosing volume while maintaining protein stability.
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 formulation provides stable bispecific proteins at low concentrations, preventing aggregation and maintaining activity during extended storage at 2-8°C and elevated temperatures, suitable for convenient transport and storage.
Implementation Method 1
a surfactant; wherein the w/w ratio of surfactant to protein is in the range of 0.75:1 to 1.5:1
Implementation Method 2
a stabiliser, wherein the ratio of stabiliser to bulking agent is greater than 1:1, and wherein the stabiliser is a disaccharide
Implementation Method 3
a bulking agent, wherein the bulking agent is a polyol
Data Source
Figure 1A~1B
Figure 1C~2A
Figure 2B~2C
AI summary
The present invention relates to a pharmaceutical formulation comprising (i) a therapeutically effective amount of a bispecific protein comprising a soluble T cell receptor (TCR) and an scFV; and (ii) a surfactant. The w/w ratio of surfactant to protein is in the range of 0.75:1 to 1.5:1. The formulation may further comprise a bulking agent and/or a stabiliser. A further pharmaceutical formulation comprises (i) a therapeutically effective amount of a bispecific protein comprising a soluble T cell receptor (TCR) and an scFV; (ii) a bulking agent; and (iii) a stabiliser. The w/w ratio of stabiliser to bulking agent may be greater than 1:1.