Search

US-20260125470-A1 - BISPECIFIC T CELL ACTIVATING ANTIGEN BINDING MOLECULES

US20260125470A1US 20260125470 A1US20260125470 A1US 20260125470A1US-20260125470-A1

Abstract

The present invention generally relates to novel bispecific antigen binding molecules for T cell activation and re-direction to specific target cells. In addition, the present invention relates to polynucleotides encoding such bispecific antigen binding molecules, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the bispecific antigen binding molecules of the invention, and to methods of using these bispecific antigen binding molecules in the treatment of disease.

Inventors

  • Marina Bacac
  • Thomas Hofer
  • Ralf Hosse
  • Christiane Neumann
  • Christian Klein
  • Ekkehard Moessner
  • Pablo Umana
  • Tina Weinzierl

Assignees

  • ROCHE GLYCART AG

Dates

Publication Date
20260507
Application Date
20250811
Priority Date
20130226

Claims (20)

  1. 1 . A T cell activating bispecific antigen binding molecule comprising (i) a first antigen binding moiety which is a Fab molecule capable of specific binding to CD3, comprising at least one heavy chain complementarity determining region (CDR) selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 and at least one light chain CDR selected from the group of SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10; (ii) a second antigen binding moiety which is a Fab molecule capable of specific binding to a target cell antigen.
  2. 2 . The T cell activating bispecific antigen binding molecule of claim 1 , wherein the first antigen binding moiety comprises a heavy chain variable region comprising an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to an amino acid sequence selected from the group of: SEQ ID NO: 3, SEQ ID NO: 32 and SEQ ID NO: 33 and a light chain variable region comprising an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence selected from the group of: SEQ ID NO: 7 and SEQ ID NO: 31.
  3. 3 . The T cell activating bispecific antigen binding molecule of claim 1 , wherein the first antigen binding moiety comprises a heavy chain variable region comprising an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7.
  4. 4 - 9 . (canceled)
  5. 10 . The T cell activating bispecific antigen binding molecule of claim 1 , wherein the first antigen binding moiety is a crossover Fab molecule wherein either the variable or the constant regions of the Fab light chain and the Fab heavy chain are exchanged.
  6. 11 . The T cell activating bispecific antigen binding molecule of claim 10 , wherein the first antigen binding moiety is a crossover Fab molecule wherein the constant regions of the Fab light chain and the Fab heavy chain are exchanged.
  7. 12 . The T cell activating bispecific antigen binding molecule of claim 1 , wherein the second antigen binding moiety is a conventional Fab molecule.
  8. 13 . The T cell activating bispecific antigen binding molecule of claim 1 , comprising not more than one antigen binding moiety capable of specific binding to CD3.
  9. 14 . The T cell activating bispecific antigen binding molecule of claim 1 , comprising a third antigen binding moiety which is a Fab molecule capable of specific binding to a target cell antigen.
  10. 15 . (canceled)
  11. 16 . The T cell activating bispecific antigen binding molecule of claim 14 , wherein the third antigen binding moiety is identical to the second antigen binding moiety.
  12. 17 - 18 . (canceled)
  13. 19 . The T cell activating bispecific antigen binding molecule of claim 1 , wherein the first and the second antigen binding moiety are fused to each other, optionally via a peptide linker.
  14. 20 - 22 . (canceled)
  15. 23 . The T cell activating bispecific antigen binding molecule of claim 1 , additionally comprising (iii) an Fc domain composed of a first and a second subunit capable of stable association.
  16. 24 - 26 . (canceled)
  17. 27 . The T cell activating bispecific antigen binding molecule of claim 23 , wherein a third antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or second subunit of the Fc domain.
  18. 28 - 35 . (canceled)
  19. 36 . The T cell activating bispecific antigen binding molecule of claim 23 , wherein the Fc domain is an IgG, specifically an IgG 1 or IgG 4 , Fc domain.
  20. 37 . (canceled)

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of U.S. patent application Ser. No. 19/028,318, filed Jan. 17, 2025, which is a divisional of U.S. patent application Ser. No. 18/763,119, filed Jul. 3, 2024, which is a divisional of U.S. patent application Ser. No. 18/529,549, filed Dec. 5, 2023, which is a divisional of U.S. patent application Ser. No. 17/306,079, filed May 3, 2021, which is a divisional of U.S. patent application Ser. No. 16/996,600, filed Aug. 18, 2020, which is a divisional of U.S. patent application Ser. No. 16/134,494, filed Sep. 18, 2018, now U.S. Pat. No. 10,781,258, issued Sep. 22, 2020, which is a divisional of U.S. patent application Ser. No. 14/188,486, filed Feb. 24, 2014, now U.S. Pat. No. 10,155,815, issued Dec. 18, 2018, which claims priority to European Application No. 13156686.1, filed Feb. 26, 2013, each of which is incorporated herein by reference in its entirety. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Jul. 29, 2025, is named 51177-0080022_Sequence_Listing_7_29_25.xml and is 182,531 bytes in size. FIELD OF THE INVENTION The present invention generally relates to bispecific antigen binding molecules for activating T cells. In addition, the present invention relates to polynucleotides encoding such bispecific antigen binding molecules, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the bispecific antigen binding molecules of the invention, and to methods of using these bispecific antigen binding molecules in the treatment of disease. BACKGROUND The selective destruction of an individual cell or a specific cell type is often desirable in a variety of clinical settings. For example, it is a primary goal of cancer therapy to specifically destroy tumor cells, while leaving healthy cells and tissues intact and undamaged. An attractive way of achieving this is by inducing an immune response against the tumor, to make immune effector cells such as natural killer (NK) cells or cytotoxic T lymphocytes (CTLs) attack and destroy tumor cells. CTLs constitute the most potent effector cells of the immune system, however they cannot be activated by the effector mechanism mediated by the Fc domain of conventional therapeutic antibodies. In this regard, bispecific antibodies designed to bind with one “arm” to a surface antigen on target cells, and with the second “arm” to an activating, invariant component of the T cell receptor (TCR) complex, have become of interest in recent years. The simultaneous binding of such an antibody to both of its targets will force a temporary interaction between target cell and T cell, causing activation of any cytotoxic T cell and subsequent lysis of the target cell. Hence, the immune response is re-directed to the target cells and is independent of peptide antigen presentation by the target cell or the specificity of the T cell as would be relevant for normal MHC-restricted activation of CTLs. In this context it is crucial that CTLs are only activated when a target cell is presenting the bispecific antibody to them, i.e. the immunological synapse is mimicked. Particularly desirable are bispecific antibodies that do not require lymphocyte preconditioning or co-stimulation in order to elicit efficient lysis of target cells. Several bispecific antibody formats have been developed and their suitability for T cell mediated immunotherapy investigated. Out of these, the so-called BiTE (bispecific T cell engager) molecules have been very well characterized and already shown some promise in the clinic (reviewed in Nagorsen and Bauerle, Exp Cell Res 317, 1255-1260 (2011)). BiTEs are tandem scFv molecules wherein two scFv molecules are fused by a flexible linker. Further bispecific formats being evaluated for T cell engagement include diabodies (Holliger et al., Prot Eng 9, 299-305 (1996)) and derivatives thereof, such as tandem diabodies (Kipriyanov et al., J Mol Biol 293, 41-66 (1999)). A more recent development are the so-called DART (dual affinity retargeting) molecules, which are based on the diabody format but feature a C-terminal disulfide bridge for additional stabilization (Moore et al., Blood 117, 4542-51 (2011)). The so-called triomabs, which are whole hybrid mouse/rat IgG molecules and also currently being evaluated in clinical trials, represent a larger sized format (reviewed in Seimetz et al., Cancer Treat Rev 36, 458-467 (2010)). The variety of formats that are being developed shows the great potential attributed to T cell re-direction and activation in immunotherapy. The task of generating bispecific antibodies suitable therefor is, however, by no means trivial, but involves a number of challenges that have to be met related to efficacy, toxicity, applicability and produceability of the antibodies.