Antibody-drug conjugates comprising anti-TM4SF1 antibodies and methods of using the same
Inventors
Jaminet, Paul A. • JAMINET, Shou-Ching S. • HA, Edward H. • Presta, Leonard G. • HUDLIKAR, Manish S.
Assignees
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Publication Number
US-12428477-B2
Publication Date
2025-09-30
Expiration Date
Abstract
Antibody-drug conjugates (ADCs) are described, comprising anti-TM4SF1 antibodies, and antigen-binding fragments thereof. Methods of use of said ADCs are also described.
Core Innovation
The document describes anti-TM4SF1 antibody-drug conjugates in which an anti-TM4SF1 antibody or an antigen binding fragment thereof is conjugated to a therapeutic molecule via a linker. The conjugate uses a human IgG1 Fc region that comprises a cysteine residue at position N297, optionally with one or more mutations selected from M252Y, S254T, and T256E, and the therapeutic molecule is conjugated to the cysteine at position 297.
The antibody component is defined by heavy-chain and light-chain CDR sets with specified amino acid sequences, including multiple alternative CDR1, CDR2, and CDR3 combinations for the heavy chain and the corresponding CDR combinations for the light chain. The document also describes humanized anti-TM4SF1 antibodies and antigen-binding fragments with sequence variants defined for specific heavy- and light-chain variable domains and CDRs, including humanized AGX-A07 and humanized AGX-A01.
A key inventive theme is modifying Fc features to improve vascular safety and therapeutic margin, including reducing effector functions associated with C1q binding, Fc receptor binding (FcγR), ADCC, and CDC. The document also emphasizes Fc engineering to increase FcRn affinity and serum half-life, and discloses IgG1 Fc region sequence variants with substitutions such as L234A/L235A/G237A with cysteine introduction at N297C, and other combinations involving P331G, K322A, E233P, and D265A.
Claims Coverage
The document provides independent claim coverage for anti-TM4SF1 ADCs with specific Fc engineering, CDR-defined antibodies, and an acetamide/C6-alkylene linker that conjugates the therapeutic molecule via the N297 cysteine. Independent claim content also covers the humanized anti-TM4SF1 antibody sequence sets and defined linker chemistry.
Anti-TM4SF1 ADC with N297 cysteine Fc engineering and acetamide/C6-alkylene linker
An antibody-drug conjugate with an anti-TM4SF1 antibody (or antigen binding fragment) conjugated to a therapeutic molecule via a linker, where the anti-TM4SF1 antibody comprises a human IgG1 Fc region with a cysteine residue at position N297, optionally with one or more mutations selected from M252Y, S254T, and T256E, and the therapeutic molecule is conjugated to the cysteine at position 297, with a linker comprising acetamide and a spacer of C6 alkylene.
CDR-defined anti-TM4SF1 heavy and light chain sequence sets
The anti-TM4SF1 antibody (or antigen binding fragment) comprises a heavy chain comprising CDR1, CDR2, and CDR3 domains and a light chain comprising CDR1, CDR2, and CDR3 domains, wherein the domains comprise one of the specified SEQ ID NO combinations listed as options.
Overall claim coverage centers on an anti-TM4SF1 ADC conjugated at an engineered N297 cysteine in a human IgG1 Fc using an acetamide/C6-alkylene linker, together with antibodies specified by multiple alternative heavy/light CDR sequence sets.
Stated Advantages
Improved vascular safety and therapeutic margin.
Reduced C1q and reduced Fc receptor/ADCC/CDC effector functions.
Increased FcRn affinity and increased serum half-life.
Documented Applications
Treating or preventing cancers and metastasis, including inflammatory indications.
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