Pierre Fabre’s DN30-Derived Fab-Fc Antibody Fragment A Monovalent MET Antagonist for Cancer Treatment

The MET oncogene drives tumour growth and metastasis in a range of solid cancers, making the Met receptor tyrosine kinase a high-priority therapeutic target. Pierre Fabre Medicament has developed a structurally engineered antibody fragment – a Fab-Fc format – that functions as a full Met antagonist while maintaining the pharmacokinetic stability needed for clinical use.

The Problem

The MET oncogene is genetically altered in 1-4% of most solid tumours, with mutations concentrated in domains critical for ligand binding and receptor signalling. MET alterations are found in non-small cell lung cancer (including exon 14 splice mutations in approximately 3% of cases), gastric cancer, renal cell carcinoma, and other solid tumours. Activated MET drives the invasive growth programme, coupling cancer cell proliferation with migration, matrix degradation, and survival under hypoxic or radiation-stressed conditions.

Several anti-Met approaches have entered clinical development, including the monoclonal antibody Onartuzumab (MetMab) from Roche. However, a fundamental problem with conventional bivalent antibodies targeting MET is their tendency to cause partial agonism: by simultaneously binding two Met receptor molecules, they can stabilise receptor complexes in a manner similar to the natural ligand HGF, inadvertently activating some of the pathways they are meant to block.

The monovalent Fab fragment of the DN30 antibody avoids this agonistic effect and acts as a full Met antagonist. However, Fab fragments have short serum half-lives because their low molecular weight causes rapid renal clearance. Earlier engineered solutions such as the DCD (Dual Constant Domain Fab) constructs improved pharmacokinetics over the plain Fab but did not reach the half-life of the original full antibody.

What This Invention Does

The patent describes an anti-Met antibody fragment that retains the single antigen-binding arm of the DN30 antibody to avoid the bivalency-related partial agonism, while attaching an Fc region to confer the in vivo stability and longer half-life associated with full IgG antibodies.

The molecule consists of three polypeptide chains. The first polypeptide is a humanised light chain comprising a humanised VL domain fused to a human CL domain, where the VL domain contains CDRs with amino acid sequences set forth in SEQ ID No. 1, 2, and 3, and the VL domain itself has the sequence of SEQ ID No. 7. The second polypeptide is a humanised heavy chain comprising a humanised VH domain, a human CH1 constant domain, and the first Fc polypeptide, which contains a hinge region, a CH2 domain, and a CH3 domain. The VH domain contains CDRs set forth in SEQ ID No. 4, 5, and 6, and the VH domain itself has the sequence of SEQ ID No. 8. The third polypeptide is a second Fc polypeptide comprising a truncated hinge region, a CH2 domain, and a CH3 domain, without any variable or antigen-binding domains – this arm contributes to the Fc region but carries no antigen-binding activity.

The result is a Fab-Fc format: one antigen-binding arm (the humanised DN30 Fab) fused to an Fc region formed by the pairing of the heavy chain Fc portion and the standalone Fc polypeptide. The single antigen-binding arm prevents the bivalent receptor clustering responsible for partial agonism, while the Fc region provides FcRn binding in tissues and prolongs serum half-life.

Key Features

Monovalent antigen binding. The single antigen-binding arm eliminates the bivalent receptor clustering that causes partial MET agonism with conventional antibodies, ensuring the molecule functions as a full antagonist rather than a partial agonist.

Humanised DN30 variable regions. The VL and VH domains are humanised versions of the murine DN30 antibody’s variable regions (SEQ ID No. 7 and 8), retaining the DN30 epitope specificity while reducing immunogenicity in human patients.

Fc region for pharmacokinetic stability. The Fc region comprising two Fc polypeptides provides FcRn receptor binding, which recycles the antibody fragment from endosomes back into circulation, substantially extending serum half-life compared to Fab-only formats.

Therapeutic activity independent of format alone. The inventors note that the improved therapeutic properties of this antibody fragment depend on the specific variable region sequences rather than simply on the monovalent format or Fc presence alone.

Combination product option. The disclosure also covers a combination product comprising the anti-Met Fab-Fc together with a decoy form of the Met extracellular domain (mutated to prevent binding by the antibody) for use as an HGF trap.

Who Is Behind It?

The applicant is Pierre Fabre Medicament of France. The named inventors are Elisa Vigna, Cristina Basilico, Tiziana Crepaldi, and Paolo Maria Comoglio – researchers associated with the Candiolo Cancer Institute and the University of Turin in Italy. This divisional was filed on 26 February 2026, derived from parent application AU 2019358417, which was filed on 7 October 2019. Phillips Ormonde Fitzpatrick in Melbourne are the Australian patent attorneys.

Why It Matters

The Fab-Fc engineering approach described in this patent solves a specific antibody pharmacology problem: how to maintain the therapeutic advantage of monovalent MET inhibition (full antagonism without partial agonism) while achieving the long half-life needed for practical clinical dosing. The DN30 antibody’s unique property of losing its partial agonism when converted to a monovalent format makes it particularly suitable for this engineering strategy.

MET-addicted tumours represent a defined patient population identifiable through tumour genomic profiling, making anti-Met agents a candidate for precision oncology approaches. As the clinical development of MET-targeting agents continues, Fab-Fc formats that combine specificity, full antagonism, and suitable pharmacokinetics represent an important class of next-generation antibody therapeutics.

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AU 2026201438 was published in the Australian Official Journal of Patents on 19 March 2026 and is open for public inspection. Patent applications represent inventions that are sought to be protected and do not necessarily reflect commercially available products.

Related Concepts

The MET oncogene encodes a receptor tyrosine kinase activated by hepatocyte growth factor (HGF). MET activation drives the invasive growth programme in numerous solid tumours, making it a compelling oncology target – but conventional bivalent antibodies risk partial agonism by cross-linking two receptor molecules simultaneously.

Antibody fragments such as Fabs retain antigen-binding specificity with reduced molecular size, but suffer short serum half-lives due to rapid renal clearance. Appending an FcRn-binding Fc region rescues pharmacokinetic stability while preserving the monovalent character that avoids MET agonism.