LAG-3 binding members
Inventors
Tuna, Mihriban • Wollerton Van Horck, Francisca • Everett, Katy Louise • Gaspar, Miguel • Kraman, Matthew • Kmiecik, Katarzyna • Fosh, Natalie
Assignees
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Publication Number
US-12187798-B2
Publication Date
2025-01-07
Expiration Date
Abstract
The present invention relates to specific binding members which bind to lymphocyte-activation gene 3 (LAG-3). The specific binding members preferably comprise a LAG-3 antigen-binding site which may be located in two or more structural loops of a CH3 domain of the specific binding member. The specific binding members of the invention find application, for example, in cancer therapy.
Core Innovation
The invention provides a specific binding member that binds to lymphocyte-activation gene 3 (LAG-3) using a LAG-3 antigen-binding site located in a CH3 domain of the specific binding member. The LAG-3 antigen-binding site comprises the amino acid sequences WDEPWGED (SEQ ID NO: 1), SNGQPENNY (SEQ ID NO: 2) and PYDRWVWPDE (SEQ ID NO: 3).
The described binding members include engineered antibody Fc fragment (Fcab) formats in which CH3 structural loops contain the LAG-3 binding-site sequences, with engineered antigen-binding sites generated via screening/affinity maturation and IMGT-numbered CH3-domain loop locations. The document also includes versions with and without LALA mutations, together with anti-FITC heavy-chain sequences, anti-mouse LAG-3/PD-L1 antibody sequences, and anti-human LAG-3 monoclonal antibodies.
High-affinity binding to human, mouse and cynomolgus LAG-3 is described, and the binding is reported to inhibit the LAG-3–MHC class II interaction. Functional activity is described in T cell activation/IL-2 release assays, and additional constructs are described for immune-cell functional evaluation. The document further describes antibodies that combine LAG-3 binding with a CDR-based antigen-binding site for an immune system modulator, including TIM-3, CTLA-4, CD73, or CSF-1R.
The document also describes combination with anti-PD-L1 that reduces LAG-3 expression on tumor-infiltrating lymphocytes (TILs) and supports reversal of T cell exhaustion. Tumor growth inhibition is described in a syngeneic MC38 mouse model when LAG-3 binding is combined with second antigen-binding sites.
Claims Coverage
The independent claims cover two core inventive categories: a LAG-3 binding member defined by a CH3-domain LAG-3 antigen-binding site specified by three amino-acid sequences, and an antibody molecule that additionally includes a CDR-based antigen-binding site for an immune system modulator. In total, two inventive feature groupings are identified.
Ch3-domain LAG-3 antigen-binding site defined by WDEPWGED, SNGQPENNY and PYDRWVWPDE
A specific binding member that binds to lymphocyte-activation gene 3 (LAG-3), comprising a LAG-3 antigen-binding site located in a CH3 domain of the specific binding member, wherein the LAG-3 antigen-binding site comprises the amino acid sequences WDEPWGED (SEQ ID NO: 1), SNGQPENNY (SEQ ID NO: 2) and PYDRWVWPDE (SEQ ID NO: 3).
Dual binding antibody with CDR-based immune-modulator site and CH3-domain LAG-3 site
An antibody molecule which binds to an immune system modulator and lymphocyte-activation gene 3 (LAG-3), wherein the antibody molecule comprises a CDR-based antigen-binding site for the immune system modulator and a LAG-3 antigen-binding site located in a CH3 domain of the antibody molecule, wherein the LAG-3 antigen-binding site comprises the amino acid sequences WDEPWGED (SEQ ID NO: 1), SNGQPENNY (SEQ ID NO: 2) and PYDRWVWPDE (SEQ ID NO: 3).
Overall claim coverage centers on CH3-domain placement of a LAG-3 antigen-binding site defined by WDEPWGED (SEQ ID NO: 1), SNGQPENNY (SEQ ID NO: 2) and PYDRWVWPDE (SEQ ID NO: 3), with one independent claim limited to that site and the other requiring an additional CDR-based antigen-binding site for an immune system modulator.
Stated Advantages
Inhibition of the LAG-3–MHC class II interaction.
Functional activity in T cell activation/IL-2 release assays.
Reduction of LAG-3 expression on tumor-infiltrating lymphocytes (TILs) when combined with anti-PD-L1.
Support for reversal of T cell exhaustion.
Tumor growth inhibition in a syngeneic MC38 mouse model when LAG-3 binding is combined with second antigen-binding sites.
Documented Applications
Treatment of cancer in a patient by administering a therapeutically effective amount of a specific binding member.
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