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EP-4739709-A1 - BINDING CONSTRUCTS

EP4739709A1EP 4739709 A1EP4739709 A1EP 4739709A1EP-4739709-A1

Abstract

The invention provides inter alia a construct comprising an LTBR binding agent and a PD-1 binding agent or a PD-L1 binding agent.

Inventors

  • JUPP, RAY
  • LEGG, James

Assignees

  • Mestag Therapeutics Ltd

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. 1 . A construct comprising (i) an LTBR binding agent and (ii) a PD-1 binding agent or a PD-L1 binding agent.
  2. 2. The construct according to claim 1 , wherein the construct comprises an antibody or fragment thereof.
  3. 3. The construct according to either claim 1 or 2, wherein the LTBR binding agent is a variable domain and the PD-1 binding agent or PD-L1 binding agent is a variable domain.
  4. 4. The construct according to any one of claims 1 to 3 wherein the LTBR binding agent specifically binds to LTBR.
  5. 5. The construct according to any one of claims 1 to 4 wherein the PD-1 binding agent specifically binds to PD-1.
  6. 6. The construct according to any one of claims 1 to 4 wherein the PD-L1 binding agent specifically binds to PD-L1.
  7. 7. The construct according to any one of claims 1 to 6 wherein the LTBR binding agent is an LTBR agonist.
  8. 8. The construct according to claim 7 wherein the LTBR agonist is an agonist of NFKB pathways.
  9. 9. The construct according to claim 8 wherein the LTBR agonist induces clustering of LTBR.
  10. 10. The construct according to either claim 8 or 9 wherein the LTBR agonist activates the classical NFKB pathway (such as leading to expression of adhesion molecules such as ICAMs, such as ICAM-1 , VCAM-1 and/or MAdCAM-1).
  11. 11 . The construct according to any one of claims 8 to 10 wherein the LTBR agonist activates the alternative NFKB pathway (such as leading to expression of chemokines, such as CCL-2, CCL-5, CCL-19, CCL-21 , CXCL-10 and/or CXCL-13).
  12. 12. The construct according to any one of claims 1 to 11 wherein the PD-1 binding agent blocks interaction of PD-1 and PD-L1.
  13. 13. The construct according to any one of claims 1 to 11 wherein the PD-L1 binding agent blocks interaction of PD-1 and PD-L1.
  14. 14. The construct according to any one of claims 1 to 13 wherein the LTBR binding agent is capable of binding LTBR on a first cell and the PD-1 binding agent or PD-L1 binding agent is capable of binding PD-1 or PD-L1 on a second cell simultaneously.
  15. 15. The construct according to any one of claims 1 to 14 wherein the LTBR binding agent is capable of binding LTBR on a cell and the PD-1 binding agent or PD-L1 binding agent is capable of binding PD-1 or PD-L1 on the same cell simultaneously.
  16. 16. The construct according to any one of claims 1 to 15 wherein the construct is a multivalent, bispecific antibody.
  17. 17. The construct according to claim 16 wherein the construct is a bivalent, bispecific antibody.
  18. 18. The construct according to any one of claims 1 to 17 wherein the construct binds to LTBR with an affinity (KD) of 1.0E-08 M or less.
  19. 19. The construct according to any one of claims 1 to 18 wherein the construct binds to PD-1 or PD-L1 with an affinity (KD) of 9.0E-10 M or less.
  20. 20. A construct according to any one of claims 1 to 19 for use in the treatment of cancer.

Description

BINDING CONSTRUCTS Field of the invention The invention relates to constructs comprising (i) an LTBR binding agent and (ii) a PD-1 binding agent or a PD-L1 binding agent, particularly for the treatment of diseases such as cancer, and related aspects. Background of the invention Cancer can affect multiple cell types and tissues but the underlying cause is a breakdown in the control of cell division. This process is highly complex, requiring careful coordination of multiple pathways, many of which remain to be fully characterised. Cancer immunotherapy involves the use of a subject's own immune system to treat or prevent cancer. These therapies are designed to provoke the body’s immune system to eliminate cancer cells and exploit the fact that cancers accumulate genetic mutations resulting in the expression of tumor antigens. These tumor antigens consist of tumor-associated antigens such as proteins and tumor-specific antigens or neoantigens, which are peptides that are presented by major histocompatibility molecules (Xie et al 2023). However, malignant tumors can evade detection by the immune system via tumor cell intrinsic mechanisms and mechanisms linked to the tumor microenvironment leading to therapy resistance (Sharma et al 2017). Checkpoint inhibitors such as, PD-1 and PD-L1 blocking antibodies, have had a significant impact on the treatment of cancer. PD-1 and PD-L1 antibodies work by blocking the interaction of PD-1 with its ligands, PD-L1 and/or PD-L2, which has been shown to enhance the antitumor activity of T-cells (Jiang et al. 2020). Durable responses to immunotherapy however, have only been observed in a minority of cancer patients and thus there is a need for the development of new therapies. Key challenges in mounting durable anti-tumor responses include limited infiltration of immune effector cells in the tumor, immune cell dysfunction and the lack of priming of anti-tumor immune cells. Recently, it has been shown that the presence of high endothelial venules (HEV) and tertiary lymphoid structures (TLS) in cancer patients is associated with better survival and with better response to therapy (Cabrita et al 2020; Vanhersecke et al 2021 ; Asrir et al 2022). HEVs are specialized structures in the vasculature that serve as portals for immune cell entry into the tumor and TLS are ectopic immune cell aggregates that provide a favourable local immune environment and facilitate local priming of immune cells (Sautes-Fridman et al 2019; Schumacher et al 2022). Therapeutic strategies aimed at enhancing both HEV and TLS in patients would therefore be advantageous to improve antitumour immune responses. Lymphotoxin beta receptor (LTBR), also known as tumour necrosis factor receptor superfamily member 3 (TNFRSF3), is a cell surface receptor for lymphotoxin involved in cytokine release and apoptosis. It is a member of the tumour necrosis factor receptor superfamily. LTBR plays a central role in the development and homeostasis of lymph nodes and secondary lymphoid organs (SLO), TLS and HEV by regulating the expression of several homeostatic lymphoid cytokines (e.g. CCL-19, CCL-21 , CXCL-13) and adhesion molecules (ICAM-1 , VCAM-1 , M AdCAM 1 ) via the NF-KB pathway (Dejardin et al. 2002, Schneider et al. 2004). LTBR is activated by two different trimeric ligands, LIGHT (TNFSF14) and lymphotoxin aip2 (LTaip2). Whereas LTai p2 is specific for LTBR, LIGHT also binds to and activates HVEM (TNFRSF14), a receptor expressed on and implicated in the regulation of immune cells (Pasero et al. 2012). It has been found that activation of LTBR by its ligands leads to ectopic formation of TLS and HEV (Schrama et al. 2001 ; Tang et al. 2017; Allen et al. 2017; Asrir et al. 2022). Presence of TLS and HEV in the tumour microenvironment typically correlates with immune infiltration and is also associated with better prognosis, suggesting that TLS and HEV are involved in anti-tumour immune responses (Dieu-Nosjean et al. 2008; Weinstein and Storkus 2015; Vanhersecke et al 2021 ; Asrir et al 2022). Therefore, activation of LTBR has the potential to promote formation of HEV and TLS in the tumour microenvironment and induce anti-tumour immune responses and improve current cancer immunotherapies. Due to the broad expression of LTBR in organisms, an agonistic LTBR binding construct capable of inducing TLS and creating an activating immune environment bears a substantial risk of causing systemic immune-related adverse events. Johansson-Percival et al. reported weight loss in mice after systemic administration of an LTBR activating compound, VTP-LIGHT (Johansson-Percival et al. 2017). Overexpression of lymphotoxin a and lymphotoxin p induced hepatotoxicity in mice (Haybaeck et al 2009). Therefore, as postulated in the prior art, a therapeutic modality which activates LTBR specifically in the tumour but not in other tissues is needed to reduce the risk of toxicity and to generate a well-tolerated drug that can be employed for combin