Soluble GP130 Muteins Enhancing Binding Activity

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Solution Overview

Problem

Current sgp130 variants lack improved binding activity for the IL-6/(s)IL-6R complex, limiting their therapeutic efficacy and requiring higher doses and increased production costs.

Innovation Solution

Mutagenesis of specific amino acid residues (Thr102, Gln113, and Asn114) in the N-terminal Ig-like domain of gp130 to enhance binding affinity, resulting in muteins like Thr102Tyr, Gln113Phe, and Asn114Leu, which form more potent sgp130Fc dimers with increased bioactivity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If wild-type sgp130Fc is used, then the structure is simple and production is easier, but binding activity is insufficient requiring higher doses

Engineering Contradiction:

Improvebinding activityVSAvoidprotein structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by mutating specific amino acid residues (Thr102, Gln113, Asn114) in the gp130 extracellular domain to enhance binding affinity. The mutations T102Y, Q113F, and N114L were identified to improve binding to the IL-6/sIL-6R complex, with the triple mutant achieving at least three-fold lower IC50 concentrations compared to wild-type sgp130Fc.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If higher doses of sgp130 are administered, then binding activity is improved, but production costs increase

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoiddosage amount

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent reduces the quantity of substance required by engineering muteins with enhanced binding affinity. The mutated sgp130Fc dimers demonstrate significantly improved binding activity, achieving at least three-fold lower IC50 concentrations compared to wild-type sgp130Fc, thereby reducing the therapeutic dosage needed while maintaining efficacy.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If more sgp130 protein is produced, then therapeutic coverage is improved, but manufacturing costs increase

Engineering Contradiction:

Improvetherapeutic coverageVSAvoidproduction cost

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent improves therapeutic coverage by enhancing the binding affinity of sgp130 muteins rather than increasing production volume. The mutated proteins exhibit significantly improved binding activity with at least three-fold lower IC50 concentrations, allowing effective therapeutic coverage at lower production scales and reduced manufacturing costs.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS8501696B2Soluble GP130 muteins with improved binding activity

Publication Date: 2013.08.06 CONARIS RES INST

AI summary

Described are soluble gp130 polypeptide monomers and dimers, wherein, in a preferred embodiment, at least one of the three amino acid residues Thr102 Gln113 or Asn114 of the N-terminal Ig-like domain of gp130 is mutated to Tyr102, Phe113 or Leu114, respectively. These mutations, alone or in combination, specifically enhance binding of gp130 to its ligand complex of interleukin-6 and soluble interleukin-6 receptor, thus increasing the biological activity of the gp130 muteins. In a particularly preferred embodiment, all three mutations are combined in the triple mutein Thr102Tyr/Gln113Phe/Asn114Leu (T102Y/Q113F/N114L). Moreover, a pharmaceutical composition containing said monomers or dimers and various medical uses are described.