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Formulations

A preparation and pharmaceutical preparation technology, applied in the field of bispecific protein and scFV pharmaceutical preparations, can solve the problems of TCR instability, low protein concentration, and maintaining protein stability are not easy

Pending Publication Date: 2021-11-12
IMMUNOCORE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Low protein concentrations are especially problematic, as even low levels of aggregation or brief contact with vial surfaces (i.e. adsorption losses) can result in significant loss of protein activity
[0004] Furthermore, unlike antibodies, TCRs are known to be inherently unstable in solution, meaning that proteins remain stable at elevated temperatures (e.g., above -30°C or -20°C, such as 2°C to 8°C) and / or during long-term storage sex is not easy

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1 - Stable Aqueous Formulation of Soluble TCR-scFv Bispecific Protein

[0074] A)

[0075] A bispecific protein comprising a soluble TCR fused to an anti-CD3 scFv was prepared using known methods (alpha chain of SEQ ID No: 45 of WO2011 / 001152, wherein amino acids 1 to 109 were replaced with SEQ ID No. 8 of WO2011001152 , and the amino acid at position 1 is A, and based on the numbering of SEQ ID No: 45, the C-terminus of the α chain is truncated by 8 amino acids from F196 to S203 (inclusive); and the SEQ ID No of WO2011 / 001152: 36 β chain, wherein the 259th to 370th residues correspond to SEQ ID No.27 of WO2011 / 001152, and the amino acids at the 1st and 2nd positions are A and I respectively), and size exclusion chromatography (SEC ) for buffer exchange to formulation buffer. The protein was then diluted to a final concentration of 0.20 ± 0.02 mg / mL using formulation buffer and bottled in a laminate airflow (LAF) bench.

[0076] Formulation buffer contained 5...

Embodiment 2

[0094] Example 2 - formulation optimization

[0095] A- Detergent Protein Ratio

[0096] The weight ratio between detergent and protein was found to be a key factor in producing stable formulations.

[0097] Evidence for this was obtained from Light Obscuration (LO) measurements, which assessed the presence of invisible particles of 2 μm and larger in size after 5 freeze-thaw cycles. The formulation buffer contained the TCR-scFv bispecific protein of Example 1A, 50 mM phosphate-citrate, 5% trehalose, 1% mannitol, and Tween 20 at one of 5 different concentrations. The pH is 6.5. The protein concentration was kept constant at 0.2 mg / ml. The measurement is performed on a PAMAS SVSS-C or equivalent particle sizer. Samples were analyzed purely with a pre-run volume of 0.4 ml and a measurement volume of 0.1 ml in triplicate. Particle counts > 2 μm, > 10 μm and > 25 μm were determined.

[0098] image 3 It is shown that when the ratio of Tween 20 to protein is 1, the count of ...

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Abstract

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.

Description

technical field [0001] The present invention relates to formulations. In particular, the present invention relates to pharmaceutical formulations of bispecific proteins comprising soluble T cell receptors (TCRs) and scFVs. Background technique [0002] Advances in biotechnology have made it possible to manufacture proteins for pharmaceutical applications. Since proteins are larger and more complex (eg, possess multiple functional groups in addition to their complex three-dimensional structure) than conventional organic and inorganic pharmaceuticals, the formulation of such proteins presents particular problems. In order for a protein to maintain its biological activity, the formulation must fully preserve the conformational integrity of at least one core sequence of amino acids of the protein while protecting multiple functional groups of the protein from degradation. A protein's degradation pathway may involve chemical instability (eg, any process that involves the modifi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K38/00A61K47/12A61K47/26
CPCA61K9/0019A61K47/12A61K47/26A61K38/177A61K39/39591A61K9/08A61K9/19A61K47/64C07K14/7051C07K16/2809A61K2039/505C07K2317/622C07K2317/31C07K2319/00A61K38/1774A61K39/395
Inventor 安迪·约翰逊马丁·艾伯纳卢卡斯·格鲁兹恩
Owner IMMUNOCORE LTD