TL1A binding proteins and methods of use
Inventors
ZHU, Eric Franklin • Shaheen, Hussam Hisham • Rios, Daniel
Assignees
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Publication Number
US-12509523-B1
Publication Date
2025-12-30
Expiration Date
Abstract
Provided herein are TL1A binding proteins (e.g., antibodies that bind TL1A) and methods of use.
Core Innovation
The disclosure relates to TL1A binding antibodies and TL1A binding proteins having antibody variable regions with specified CDR1, CDR2, and CDR3 amino acid sequences in a heavy chain variable region and a light chain variable region, including multiple alternative VH/VL sequence sets and sequence identity constraints. The disclosure also characterizes TL1A epitope residues on TL1A polypeptides including SEQ ID NO:2493 and SEQ ID NO:2494, and describes binding to defined TL1A epitope residue subsets and monomer or trimer forms.
The TL1A binding proteins are further described with optional immunoglobulin Fc domain inclusion and Fc modifications. Named Fc modifications include L234A/L235A (LALA) and/or M252Y, S254T, T256E (YTE), with half-life extension, modulation of effector functions, and pH 6.0-dependent effects described for Fc variants.
The disclosure also states improved developability and solubility suitable for high-concentration subcutaneous formulations, as well as binding affinity values such as Kd values below 0.5 nM and below 0.4 nM, improved binding relative to a comparator, and reduced TL1A-induced apoptosis. It further includes injectable liquid compositions containing a TL1A binding protein and a pharmaceutically acceptable carrier, with subcutaneous and intravenous administration contexts.
Claims Coverage
The consolidated claim coverage includes two independent claims directed to TL1A binding proteins defined by specified antibody variable-region CDR amino-acid sequences, with alternative VH/VL CDR sequence sets in one claim and a fixed VH/VL CDR set in the other. Additional dependent claim features narrow sequence identity, Fc class, modified Fc content, half-life extension, and an injectable liquid composition.
Specified TL1A-binding antibody variable regions with alternative CDR sequence sets
A TL1A binding protein comprising a TL1A binding antibody variable region with a heavy chain variable region (VH) having CDR1, CDR2, and CDR3 amino acid sequences according to specified SEQ ID NOs, and a light chain variable region (VL) having CDR1, CDR2, and CDR3 amino acid sequences according to specified SEQ ID NOs, including multiple alternative VH/VL pairings.
Specified TL1A-binding antibody variable regions with fixed VH and VL CDR sequences
A TL1A binding protein comprising a heavy chain variable region (VH) having CDR1, CDR2, and CDR3 amino acid sequences according to specified SEQ ID NOs, and a light chain variable region (VL) having CDR1, CDR2, and CDR3 amino acid sequences according to specified SEQ ID NOs.
The independent claims cover TL1A binding proteins defined by specific heavy-chain and light-chain variable-region CDR amino-acid sequences, with multiple alternatives in one claim and fixed sequences in the other. The dependent claim material further adds sequence identity requirements, Fc format limitations, modified Fc substitutions for half-life extension, and an injectable liquid composition.
Stated Advantages
Reduced TL1A-induced apoptosis.
Improved binding compared with a comparator.
Binding affinity with disclosed Kd values below 0.5 nM and below 0.4 nM.
Half-life extension via a modified Fc domain.
Modulates effector functions.
Provides pH 6.0-dependent effects and higher-affinity variants at pH 6.0.
Addresses TL1A-targeting binding proteins in inflammatory diseases linked to TL1A, where current TNF therapies have serious side effects.
Improved developability and solubility suitable for high-concentration subcutaneous formulations.
Markedly extends serum half-life.
Enhance or alter effector functions such as ADCC and CDC via Fc engineering, including Fcγ receptors and complement (C1q).
Reduced fucosylation, including via Asn 297 reduction.
Documented Applications
Treatment context for inflammatory diseases linked to TL1A, including Crohn’s disease and ulcerative colitis.
Therapeutic use for psoriasis.
Therapeutic use for psoriatic arthritis.
Therapeutic use for hidradenitis suppurativa.
Other gastrointestinal inflammatory conditions and related disorders, including immune checkpoint inhibitor-related colitis and Intestinal Acute Graft Versus Host Disease (aGVHD).
Inflammatory disease contexts including Type 1 diabetes.
Use in injectable liquid compositions containing a TL1A binding protein and a pharmaceutically acceptable carrier.
Subcutaneous administration of a therapeutically effective amount.
Intravenous administration of a therapeutically effective amount.
High-concentration subcutaneous formulations, including subcutaneous administration contexts such as an autoinjector.
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