Anti-TM4SF1 antibodies and methods of using same
Inventors
Jaminet, Paul A. • JAMINET, Shou-Ching S. • Dvorak, Harold F. • Presta, Leonard G.
Assignees
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Publication Number
US-11208495-B2
Publication Date
2021-12-28
Expiration Date
Abstract
Anti-TM4SF1 antibodies, and antigen-binding fragments thereof, are described that bind to an epitope on the ECL2 loop of human TM4SF1. Methods of use of said antibodies and fragments are also described, including for the inhibition of metastasis.
Core Innovation
The invention relates to anti-TM4SF1 binding proteins that specifically bind human TM4SF1, including antigen-binding fragments and full-length antibody formats. The binding proteins are defined by heavy chain variable domain and light chain variable domain sequences, including specified CDR1, CDR2, and CDR3 amino acid sequences and sequence identity relationships referenced by SEQ ID NOs. The approach defines binding proteins with an epitope on the human TM4SF1 ECL2 loop.
The invention further specifies binding properties including binding modes that are independent of ECL2 loop glycosylation, with stated affinity thresholds and binding to cynomolgus TM4SF1. It also includes Fc engineering to reduce or ablate ADCC and/or CDC effector function through specified Fc region mutation sets, together with sequence-defined variants that maintain binding characteristics.
The scope includes different immunoglobulin isotypes and formats such as IgG1, IgG2, and IgG4, as well as humanized variants and antigen-binding fragment formats including Fab, Fab’, F(ab’)2, Fv, and scFv. Antibody-drug conjugate formats are also described.
In therapeutic context, the invention describes anti-TM4SF1 antibodies and fragments for anti-metastasis applications, including inhibition of tumor cell attachment and transendothelial migration and metastatic spread through lymphatic and hematogenous routes. Pharmaceutical compositions and antigen-binding protein/fragment production approaches are described, with stated performance advantages versus a hybridoma-derived comparator (PTA-120523).
Claims Coverage
The document provides two independent claims centered on sequence-defined anti-TM4SF1 binding proteins. Across these claims, the coverage includes 2 inventive features.
Cdr-defined heavy and light chain variable domains
An anti-TM4SF1 binding protein with a heavy chain variable domain including CDR3 comprising the amino acid sequence of SEQ ID NO: 96, CDR2 comprising the amino acid sequence of SEQ ID NO: 95, and CDR1 comprising the amino acid sequence of SEQ ID NO: 94, together with a light chain variable domain including CDR3 comprising the amino acid sequence of SEQ ID NO: 110 or 111, CDR2 comprising the amino acid sequence of SEQ ID NO: 109, and CDR1 comprising the amino acid sequence of SEQ ID NO: 107 or 108.
Selected heavy-chain and light-chain amino-acid sequences
An anti-TM4SF1 binding protein in which the heavy chain is selected from the group consisting of SEQ ID NOs: 90, 92, 130 and 132, and the light chain is selected from the group consisting of SEQ ID NOs: 97, 99, 101, 103, 105, 131, and 133.
Across the independent claims, the coverage is concentrated on sequence-defined anti-TM4SF1 binding proteins defined either by fixed heavy- and light-chain CDR assignments or by selection of permitted heavy-chain and light-chain amino-acid sequences.
Stated Advantages
Reduce or ablate ADCC and CDC effector function through Fc region engineering.
ECL2-loop epitope binding with defined K_D thresholds as measured by flow cytometry.
Bind TM4SF1 without relying on glycosylation of the ECL2 loop.
Improved binding affinity/specificity versus PTA-120523.
Reduced immunogenicity via HLA binding.
Improved stability.
Reduced aggregation.
Improved solubility/manufacturability/developability.
Documented Applications
Treatment concepts targeting endothelial cell–tumor cell interactions to inhibit metastasis.
Treatment concepts targeting endothelial cell–leukocyte interactions for inflammatory disease treatment.
Tumor metastasis lung context described in relation to TM4SF1 and endothelial microdomains.
Anti-metastasis use by inhibition of tumor cell attachment and transendothelial migration.
Prevention and treatment of inflammatory disease/cancer.
Metastasis treatment related to lymphatic and hematogenous routes, including metastatic-risk settings (lung and other organs).
Use as pharmaceutical compositions containing the antibody/fragment embodiments.
Use as antibody drug conjugates including an antigen-binding protein consisting of the anti-TM4SF1 binding protein and a therapeutic molecule.
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