Multivalent VHH Polypeptides for VEGF and bFGF Inhibition

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Solution Overview

Problem

Current VHH-based therapies for angiogenesis, such as those targeting VEGF and bFGF, face challenges including antigenicity, low molecular weight leading to rapid elimination, and the need to target multiple growth factor/receptor systems, with no effective humanized monospecific or bispecific multivalent VHH-like polypeptides available.

Innovation Solution

Development of polypeptides comprising single domain antibody fragments (VHH) with specific amino acid sequences (SEQ ID NO: 23-28) that bind to VEGF or bFGF, including monovalent, bivalent, and bispecific forms, stabilized by Fc domains, to enhance bioavailability and tissue access, and inhibit receptor interactions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Volume of moving object

If VHH polypeptides are used to target angiogenic factors, then tissue penetration and solubility are improved, but molecular weight is reduced leading to rapid elimination

Engineering Contradiction:

Improvetissue penetrationVSAvoidcirculation time

Core Design Contradiction:

Volume of moving objectVSDuration of action of moving object

Solution Approach 1:

The patent combines multiple VHH polypeptides into multivalent constructs (bivalent, bispecific, or multspecific) linked by peptide linkers. This merging increases the effective molecular weight and extends circulation time while maintaining the superior tissue penetration properties of individual VHH domains. The multivalent structure allows simultaneous targeting of multiple growth factors or receptors.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The invention creates composite polypeptide structures by fusing VHH domains with Fc regions of human immunoglobulins (IgG1, IgG2, or IgG4). This composite construction combines the high tissue penetration of VHH with the extended circulation half-life of Fc-containing antibodies, resolving the contradiction between small size and rapid elimination.

Inventive Principle:

Principle #40Composite materials

2Reliability

If monoclonal antibodies are used for therapeutic treatment, then antigen binding specificity is improved, but production complexity and cost increase

Engineering Contradiction:

Improveantigen binding specificityVSAvoidproduction complexity

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent extracts only the antigen-binding VHH domain from full monoclonal antibodies, discarding the complex Fc region and other antibody components. This extracted VHH domain retains full antigen-binding specificity but can be produced much more simply in bacterial expression systems, dramatically reducing manufacturing complexity and cost.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention changes the molecular parameters of the therapeutic agent by using simplified VHH polypeptides instead of full-sized monoclonal antibodies. These VHH domains can be expressed in simpler bacterial systems at lower cost while maintaining antigen-binding specificity, and can be further modified through multivalent or Fc-fused constructions to optimize pharmacokinetic properties.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If VHH polypeptides are engineered to target multiple growth factors, then therapeutic efficacy is improved, but polypeptide complexity increases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidpolypeptide structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent designs multivalent and multispecific VHH polypeptides that can simultaneously bind multiple different growth factors (VEGF, bFGF, PDGF) or their receptors. These universal constructs provide broad antiangiogenic activity against multiple therapeutic indications, improving therapeutic efficacy while using a platform technology that can be adapted to different target combinations through modular assembly of VHH domains.

Inventive Principle:

Principle #6Universality (Multi-functionality)

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 polypeptides demonstrate increased antiangiogenic, antitumor, and immunorestorative effects with improved tissue penetration and prolonged circulation, showing superior efficacy in tumor and macular neovascularization models.

Implementation Method 1

polypeptides that bind to proangiogenic growth factors such as human vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) and inhibit their biological effects

Methodology Applied

Scientific EffectAntigen-antibody binding: Absorption (physical)

Data Source

PatentUS20250326826A1Polypeptides that bind proangiogenic growth factors

Publication Date: 2025.10.23 CENT DE ING GENETICA & BIOTECNOLOGIA

AI summary

Polypeptides that bind to proangiogenic growth factors comprising in their amino acid sequence at least one single domain antibody fragment (VHH) and vector encoding a polypeptide that binds to proangiogenic growth factors. A pharmaceutical composition comprising said polypeptide or said vectors encoding a polypeptide that binds to proangiogenic growth factors. Use of the polypeptides that bind to proangiogenic growth factors, or of the vector encoding said polypeptides, for the manufacture of a medicament. Method of treating a pathology that occurs with increased angiogenesis, inflammation, or immunosuppression, in an individual who needs it, by the administration of a therapeutically effective amount of a pharmaceutical composition comprising at least a polypeptide that bind to proangiogenic growth factors or the vector encoding said polypeptide.