Antigen binding proteins specifically binding PRAME
Inventors
Pszolla, Gabriele • Hofmann, Martin • Hutt, Meike • Bunk, Sebastian • Unverdorben, Felix • Schwoebel, Frank • Maurer, Dominik • JAWORSKI, Maike • Wagner, Claudia • SCHWOERER, Florian • Schuster, Heiko
Assignees
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Publication Number
US-12570760-B2
Publication Date
2026-03-10
Expiration Date
Abstract
The present invention concerns antigen binding proteins directed against PRAME protein-derived antigens. The invention in particular provides antigen binding proteins which are specific for the tumor expressed antigen PRAME, wherein the tumor antigen comprises or consists of SEQ ID NO: 50 and is in a complex with a major histocompatibility complex (MHC) protein. The antigen binding proteins of the invention contain, in particular, the complementary determining regions (CDRs) of novel engineered T cell receptors (TCRs) that specifically bind to said PRAME peptide. The antigen binding proteins of the invention are for use in the diagnosis, treatment and prevention of PRAME expressing cancerous diseases. Further provided are nucleic acids encoding the antigen binding proteins of the invention, vectors comprising said nucleic acids, recombinant cells expressing the antigen binding proteins and pharmaceutical compositions comprising the antigen binding proteins of the invention.
Core Innovation
The invention provides an antigen binding protein specifically binding to a PRAME antigenic peptide comprising the amino acid sequence SLLQHLIGL of SEQ ID NO: 50 when the antigenic peptide is in a complex with a major histocompatibility complex (MHC) protein. The antigen binding protein includes a first polypeptide comprising a variable domain (VA) and a second polypeptide comprising a variable domain (VB), and binding specificity is defined by complementarity determining regions (CDRs) in VA and VB.
The VA comprises CDRa1 comprising VKEFQD (SEQ ID NO: 16), CDRa2 comprising FGPYGKE (SEQ ID NO: 32), and CDRa3 comprising ALYNNYDMR (SEQ ID NO: 34). The VB comprises CDRb1 comprising SGHNS (SEQ ID NO: 10), CDRb2 comprising FQNTAV (SEQ ID NO: 36), and CDRb3 comprising ASSPGATDKQY (SEQ ID NO: 48), with framework-region selections and specified framework-region sequences for VA and VB.
Framework-region mutations are used in a PRAME-004/MHC TCR-derived antigen-binding protein to increase stability, pairing, and peptide-MHC affinity. The disclosure further includes off-target similar peptide binding limitations, Kd windows, multispecific/TCER or scTCR formats, nucleic acid, vector, host cell, and pharmaceutical composition embodiments, and use directed to cancer.
Claims Coverage
The provided material identifies one independent claim directed to an antigen binding protein for PRAME peptide binding in an MHC complex. Dependent claims refine specificity, framework definitions, off-target binding limits, production, and treatment context.
PRAME peptide-specific MHC complex antigen binding protein defined by VA and VB CDRs
An antigen binding protein specifically binding to a PRAME antigenic peptide comprising the amino acid sequence SLLQHLIGL of SEQ ID NO: 50 in a complex with an MHC protein, the antigen binding protein comprising a first polypeptide with VA CDRa1=VKEFQD (SEQ ID NO: 16), CDRa2=FGPYGKE (SEQ ID NO: 32), and CDRa3=ALYNNYDMR (SEQ ID NO: 34), and a second polypeptide with VB CDRb1=SGHNS (SEQ ID NO: 10), CDRb2=FQNTAV (SEQ ID NO: 36), and CDRb3=ASSPGATDKQY (SEQ ID NO: 48).
Off-target similar peptide binding limitation in an MHC complex
An antigen binding protein that, when in complex with an MHC protein, does not significantly bind to specified similar peptides, including an optional limitation that it does not significantly bind to IFT17-003.
Framework-region selections and sequence restrictions for VA and VB
The antigen binding protein further comprises VA and VB variable-region framework regions including selected framework regions FR1-a/FR2-a/FR3-a/FR4-a and FR1-b/FR2-b/FR3-b/FR4-b with specified amino acid sequences or sequences at least 90% identical, optionally with certain specified amino acid substitutions at indicated positions.
Production of the antigen binding protein using host-cell expression
A method for producing an antigen binding protein by providing a host cell, introducing a genetic construct encoding the protein, and expressing it in the host cell, with optional isolation and purification and optional reconstitution in a T cell.
Cancer treatment use with specified cancer types
A method for treating a cancer patient by administering the pharmaceutical composition, where the cancer is selected from a specified list of cancer types.
Strict identity constraints for VA and VB sequences in the treatment method context
The treatment method is defined such that VA contains an amino acid sequence at least 100% identical to SEQ ID NO: 132 and VB contains an amino acid sequence at least 100% identical to SEQ ID NO: 135.
The claim coverage centers on a PRAME antigenic peptide (SLLQHLIGL) binding antigen binding protein defined by specific CDR sequences in VA and VB, with further refinements including off-target similar peptide binding limitations, framework-region selections with sequence restrictions, host-cell production, administration as a pharmaceutical composition for a specified set of cancer types, and strict identity constraints for VA and VB in the treatment method.
Stated Advantages
High binding affinity (KD in low nM/pM range).
Improved solubility/stability.
Reduced functional response and detection against a panel of similar peptides, including IFT17-003.
Selective cytotoxicity toward PRAME-positive cells/lines.
In vivo tumor growth inhibition at low doses.
Increased stability, pairing, and peptide-MHC affinity for the PRAME-004/MHC TCR-derived antigen-binding protein.
Provides substantially weaker binding to off-target peptides.
Demonstrates in vitro cytotoxicity against PRAME-004-loaded T2 cells, with subpicomolar EC50 at higher peptide loading.
Limited cytotoxicity toward multiple HLA-A*02+ normal cell types and safety windows relative to PRAME-004-positive tumor cells.
Defines antigen binding specificity by Kd windows and by motif determination for PRAME-004 positions.
Documented Applications
Therapeutic use for treating cancer patients for a specified list of cancer types, including acute myeloid leukemia, breast cancer, cholangiocellular carcinoma, gallbladder cancer, glioblastoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, melanoma, amelanotic melanoma, non-Hodgkin lymphoma, non-small cell lung cancer adenocarcinoma, non-small cell lung cancer, squamous cell non-small cell lung cancer, ovarian cancer, esophageal cancer, renal cell carcinoma, small cell lung cancer, urinary bladder carcinoma, uterine and endometrial cancer, osteosarcoma, chronic lymphocytic leukemia, colorectal carcinoma, and synovial sarcoma.
Therapeutic and diagnostic uses are referenced.
Production using host cell expression of a genetic construct encoding the antigen binding protein, with optional isolation/purification and optional reconstitution in a T cell [procedural detail omitted for safety].
Use as an antigen binding protein in a complex with a major histocompatibility complex (MHC) to bind a PRAME antigenic peptide.
Production of the antigen binding protein using host-cell expression, with optional isolation and purification and optional reconstitution in a T cell.
Treatment of a cancer patient by administering a pharmaceutical composition, with cancer selected from a specified list of cancer types.
Binding assays measuring interaction with the HLA-A*02/PRAME-004 complex versus defined off-target peptides using binding kinetics analysis.
In vitro cytotoxicity assays using PRAME-004-loaded T2 cells with LDH-release readouts.
Safety assessment experiments evaluating limited cytotoxicity toward multiple HLA-A*02+ normal cell types.
LC-MS determination of PRAME-004 peptide detection frequencies on primary tumors.
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