Antigen binding proteins specifically binding PRAME

Patent metadata

Field	Value
Publication number	US-12570760-B2
Application number	US-202217736882-A
Country	US
Kind code	B2
Filing date	May 4, 2022
Priority date	May 5, 2021
Publication date	Mar 10, 2026
Grant date	Mar 10, 2026

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.

First claim

The invention claimed is:

1 . An antigen binding protein specifically binding to a PRAME antigenic peptide that comprises the amino acid sequence SLLQHLIGL of SEQ ID NO: 50 and is in a complex with a major histocompatibility complex (MHC) protein, the antigen binding protein comprising
(a) a first polypeptide comprising a variable domain (VA) comprising complementarity determining regions (CDRs) CDRa1, CDRa2 and CDRa3, wherein
the CDRa1 comprises the amino acid sequence VKEFQD (SEQ ID NO: 16), and
the CDRa3 comprises the amino acid sequence of ALYNNYDMR (SEQ ID NO: 34), and
the CDRa2 comprises the amino acid sequence FGPYGKE (SEQ ID NO: 32), and
(b) a second polypeptide comprising a variable domain (VB) comprising CDRb1, CDRb2 and CDRb3, wherein
the CDRb1 comprises the amino acid sequence SGHNS (SEQ ID NO: 10), and
the CDRb3 comprises the amino acid sequence ASSPGATDKQY (SEQ ID NO: 48), and
the CDRb2 comprises the amino acid sequence FQNTAV (SEQ ID NO: 36).

2 . The antigen binding protein of claim 1 , wherein said antigen binding protein specifically binds to a functional epitope consisting of SEQ ID NO: 50.

3 . The antigen binding protein of claim 1 , wherein said antigen binding protein does not significantly bind to at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 20 or all similar peptides selected from the group consisting of TMED9-001 (SEQ ID NO: 51), CAT-001 (SEQ ID NO: 52), DDX60L-001 (SEQ ID NO: 53), LRRC70-001 (SEQ ID NO: 54), PTPLB-001 (SEQ ID NO: 55), HDAC5-001 (SEQ ID NO: 56), VPS13B-002 (SEQ ID NO: 57), ZNF318-001 (SEQ ID NO: 58), CCDC51-001 (SEQ ID NO: 59), IFT17-003 (SEQ ID NO: 60), DIAPH1-004 (SEQ ID NO: 62), FADS2-001 (SEQ ID NO: 63), FRYL-003 (SEQ ID NO: 64), GIMAP8-001 (SEQ ID NO: 65), HSF1-001 (SEQ ID NO: 66), KNT-001 (SEQ ID NO: 67), MAU-001 (SEQ ID NO: 68), MCM4-001 (SEQ ID NO: 69), MPPE1-001 (SEQ ID NO: 71), MYO1B-002 (SEQ ID NO: 72), PRR12-001 (SEQ ID NO: 73), PTRF-003 (SEQ ID NO: 74), RASGRP1-001 (SEQ ID NO: 75), SMARCD1-001 (SEQ ID NO: 76), TGM2-001 (SEQ ID NO: 77), VAV1-001 (SEQ ID NO: 78), VIM-009 (SEQ ID NO: 317), FARSA-001 (SEQ ID NO: 306), ALOX15B-003 (SEQ ID NO: 304), FAM114A2-002 (SEQ ID NO: 305), GPR56-002 (SEQ ID NO: 307), IGHD-002 (SEQ ID NO: 308), NOMAP-3-0972 (SEQ ID NO: 309), NOMAP-3-1265 (SEQ ID NO: 310), NOMAP-3-1408 (SEQ ID NO: 311), NOMAP-3-1587 (SEQ ID NO: 312), NOMAP-3-1768 (SEQ ID NO: 313), NOMAP-5-0765 (SEQ ID NO: 314), PDCD10-004 (SEQ ID NO: 315), TSN-001 (SEQ ID NO: 316), ARMC9-002 (SEQ ID NO: 187), CLI-001 (SEQ ID NO: 188), COPG1-001 (SEQ ID NO: 190), COPS7A-001 (SEQ ID NO: 192), EIF-009 (SEQ ID NO: 194), EXT2-006 (SEQ ID NO: 196), LMNA-001 (SEQ ID NO: 198), PKM-005 (SEQ ID NO: 200), PSMB3-002 (SEQ ID NO: 202), RPL-007 (SEQ ID NO: 204), SPATS2L-003 (SEQ ID NO: 206), SYNE1-002 (SEQ ID NO: 208), TGM2-002 (SEQ ID NO: 210) and TPR-004 (SEQ ID NO: 212), in a complex with a MHC protein, optionally said antigen binding protein does not significantly bind to IFT17-003 (SEQ ID NO: 60) in a complex with a MHC protein.

4 . The antigen binding protein of claim 1 , wherein the antigen binding protein is multispecific.

5 . The antigen binding protein of claim 1 , wherein
the first and the second polypeptide are comprised in a single polypeptide chain or two polypeptide chains, optionally wherein VA is comprised in a first polypeptide chain and VB is comprised in a second polypeptide chain; and/or the variable domain VA is a Vα or Vγ domain and the variable domain VB is a Vβ or Vδ domain.

6 . The antigen binding protein of claim 1 , wherein
the VA further comprises one or more framework regions, optionally all framework regions, selected from the group consisting of FR1-a, FR2-a, FR3-a and FR4-a, wherein
FR1-a comprises the amino acid sequence of SEQ ID NO: 345 or SEQ ID NO: 346, or an amino acid sequence at least 90% identical to SEQ ID NO: 345, optionally comprising K or N, optionally K, at position 20 and/or L or M, optionally L, at position 2;
FR2-a comprises the amino acid sequence of SEQ ID NO: 347 or SEQ ID NO: 348, or an amino acid sequence at least 90% identical to SEQ ID NO: 347, optionally comprising L, I or M, optionally L or I, at position 39, A or D, optionally A, at position 47, K or W, optionally K, at position 44, F or A, optionally F, at position 52 and/or Y or V, preferably Y, at position 55;
FR3-a comprises the amino acid sequence of SEQ ID NO: 349 or an amino acid sequence at least 90% identical to SEQ ID NO: 349, optionally comprising T or K, optionally T, at position 92 and/or D or G, optionally D, at position 93;
FR4-a comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence at least 90% identical to SEQ ID NO: 350; and
the VB further comprises one or more framework regions, optionally all framework regions, selected from the group consisting of FR1-b, FR2-b, FR3-b and FR4-b, wherein
FR1-b comprises the amino acid sequence of SEQ ID NO: 351 or SEQ ID NO: 352 or an amino acid sequence at least 90% identical to SEQ ID NO: 351, optionally comprising H or N, optionally H, at position 10, E, L or K, preferably E, at position 11 and/or R or H, at position 22;
FR2-b comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence at least 90% identical to SEQ ID NO: 353, optionally comprising R or K, optionally R, at position 43, E or Q, optionally E, at position 44, M or P, optionally P, at position 46, and/or R or Q, optionally Q, at position 48;
FR3-b comprises the amino acid sequence of SEQ ID NO: 354 or SEQ ID NO: 355 or an amino acid sequence at least 90% identical to SEQ ID NO: 354, optionally comprising D, A, E, R, K Q, Nor S, optionally D, A, E, Q, N or S, optionally D or A, optionally D, at position 84; and
FR4-b comprises the amino acid sequence of SEQ ID NO: 356 or an amino acid sequence at least 90% identical to SEQ ID NO: 356.

7 . The antigen binding protein of claim 1 , wherein
the VA comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence at least 85% identical to SEQ ID NO: 132; and the VB comprises the amino acid sequence of SEQ ID NO: 135 or an amino acid sequence at least 85% identical to SEQ ID NO: 135.

8 . The antigen binding protein of claim 1 , further comprising an antibody light chain variable domain (VL) and an antibody heavy chain variable domain (VH), wherein optionally wherein the VL and the VH bind to an α/β TCR/CD3 complex.

9 . The antigen binding protein of claim 8 , wherein the antigen binding protein comprises a first and a second polypeptide chain, and wherein
the first polypeptide chain is represented by a formula [Ia]:
V1-L1-D1-L2-V2-L3-D2  [Ia],

and the second polypeptide chain is represented by a formula [IIa]
V3-L4-D3-L5-V4-L6-D4  [IIa],

wherein
V1, V2, V3, and V4 are variable domains, wherein one of V1 to V4 is VA, one is VB, one is VL and one is VH;
D1, D2, D3, and D4 are dimerization domains and may be present or absent, wherein D1 and D3, and D2 and D4, specifically bind to each other and at least one pair of D1 and D3, or D2 and D4 is present; and
L1, L2, L3, L4, L5, and L6 are linkers, wherein L1 and L4 are present and L2, L3, L5, and L6 may be present or absent.

10 . The antigen binding protein of claim 1 , comprising
the first polypeptide selected from SEQ ID NO: 158, and the second polypeptide selected from SEQ ID NO: 300.

11 . An isolated nucleic acid comprising a sequence encoding the antigen binding protein of claim 1 .

12 . A vector comprising the nucleic acid of claim 11 .

13 . A host cell comprising the vector of claim 12 , optionally wherein the host cell is a lymphocyte, optionally a

Assignees

• Immatics Biotechnologies Gmbh

Inventors

• Pszolla Gabriele
• Hofmann Martin
• Hutt Meike
• Bunk Sebastian
• Unverdorben Felix
• Schwoebel Frank
• Maurer Dominik
• Jaworski Maike
• Wagner Claudia
• Schwoerer Florian
• Schuster Heiko

Classifications

• A61K39/001189

  PRAME · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/31

  multispecific · CPC title