US-12617851-B2 - TREM2 antibodies and uses thereof

Abstract

The present invention relates to TREM2 antibodies, and uses thereof, for treating diseases such as neurodegenerative diseases.

Inventors

• Forest Hoyt Andrews
• Ross Edward Fellows
• Ying Tang
• Yaming Wang

Assignees

• ELI LILLY AND COMPANY

Dates

Publication Date

20260505

Application Date

20220505

Claims (4)

1. 1 . An antibody that binds Triggering receptors expressed on myeloid cells 2 (TREM2), comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3, and the HCVR comprises CDRs HCDR1, HCDR2, and HCDR3, and wherein the LCDR1 has the amino acid sequence of SEQ ID NO: 1, the LCDR2 has the amino acid sequence of SEQ ID NO: 2, the LCDR3 has the amino acid sequence of SEQ ID NO: 3, the HCDR1 has the amino acid sequence of SEQ ID NO: 4, the HCDR2 has the amino acid sequence of SEQ ID NO: 5, and the HCDR3 has the amino acid sequence of SEQ ID NO: 6.
2. 2 . The antibody of claim 1 , wherein the LCVR has the amino acid sequence of SEQ ID NO: 7, and the HCVR has the amino acid sequence of SEQ ID NO: 8.
3. 3 . The antibody of claim 1 , wherein the antibody comprises a LC and a HC, and wherein the LC has the amino acid sequence of SEQ ID NO: 9, and the HC has the amino acid sequence of SEQ ID NO: 10.
4. 4 . A pharmaceutical composition comprising the antibody of claim 1 , and one or more pharmaceutically acceptable carriers, diluents, or excipients.

Description

The present invention is in the field of medicine. More particularly, the present invention relates to antibodies that bind to TREM2, compositions comprising such TREM2 antibodies, and methods of using such TREM2 antibodies for the treatment of neurodegenerative diseases such as Alzheimer's disease. Triggering receptors expressed on myeloid cells 2 (TREM2) is a cell surface transmembrane glycoprotein that is expressed in myeloid cells such as dendritic cells, granulocytes, and tissue-specific macrophages such as osteoclasts, Kuppfer cells, and alveolar macrophages. The TREM2 transmembrane region associates with the adaptor proteins DAP12 and DAP10, and TREM2 signaling through adaptor proteins results in activation of downstream targets such as mTOR and MAPK. TREM2 activation therefore results in activities such as increased proliferation, survival, phagocytosis, phagocytic oxidative burst with production of reactive oxygen species (ROS), as well as pro- and anti-inflammatory cytokine expression. Upon activation of myeloid cells under certain circumstances, membrane-bound TREM2 may be cleaved by proteases, thereby resulting in the release of soluble TREM2. TREM2 has been implicated in neurodegenerative diseases such as Alzheimer's disease. TREM2 is expressed by microglia in the brain, and increased expression of TREM2 has been observed in Alzheimer's disease patients and in mouse models of tau pathology. Moreover, TREM2 mutations are associated with neurodegenerative diseases and TREM2 knock-out mice have been shown to be protected against age-related inflammatory changes, accumulation of oxidized lipids, and loss of neuronal structures (see, e.g., Gerlach, et al., TREM2 triggers microglial density and age-related neuronal loss. Glia, 67(3):539-550 (2019)). TREM2 deficiency may also be neuroprotective in reducing hippocampal volume loss after traumatic brain injury (see, Saber, et al., Triggering Receptor Expressed on Myeloid Cells 2 Deficiency Alters Acute Macrophage Distribution and Improves Recovery after Traumatic Brain Injury, J. Neurotrauma, 34:423-435 (2017)). TREM2 antibodies are known in the art. For example, PCT publication number WO 2016/023019 and PCT publication number WO 2019/028292 disclose TREM2 antibodies. Such antibodies may cluster and activate TREM2 in vivo, and/or bind human TREM2 with nanomolar affinity. Thus, there still exists a need for alternative TREM2 antibodies that 1) bind human TREM2 with desirable high affinity and association and dissociation rates for optimal activity, 2) reduce microglia activation state and/or promote microglia homeostasis without affecting total microglia numbers (e.g., no impact on survival), 3) inhibit TREM2 signaling, 4) achieve in vivo efficacy, 5) demonstrate low immunogenic potential, and/or 6) demonstrate suitable developability characteristics such as stability, solubility, low self-association, and pharmacokinetic characteristics which are acceptable for development and/or use in the treatment of neurodegenerative disorders. Accordingly, the present invention provides novel TREM2 antibodies that bind human TREM2 with high affinity. Antibodies of the present invention are considered to provide a means to promote microglia homeostasis. Antibodies of the present invention also have at least one of the following properties of reducing microglia activation state, and/or restoring microglia homeostasis, without affecting total microglia numbers (e.g., not impacting on survival), preventing macrophage phagocytosis, inhibiting TREM2 signaling, achieving in vivo efficacy, demonstrating low immunogenic potential, and/or demonstrating suitable developability characteristics for clinical development and/or use in the treatment of neurodegenerative disorders. Such antibodies may be useful in the treatment of neurodegenerative diseases such as Alzheimer's disease, and may be therapeutically effective at lower doses or less frequent dosing. In an embodiment, the present invention provides an antibody that binds TREM2, comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3, and the HCVR comprises CDRs HCDR1, HCDR2, and HCDR3, and wherein LCDR1 has an amino acid sequence given by SEQ ID NO: 1, LCDR2 has an amino acid sequence given by SEQ ID NO: 2, LCDR3 has an amino acid sequence given by SEQ ID NO: 3, HCDR1 has an amino acid sequence given by SEQ ID NO: 4, HCDR2 has an amino acid sequence given by SEQ ID NO: 5, and HCDR3 has an amino acid sequence given by SEQ ID NO: 6. In an embodiment, the LCVR has an amino acid sequence given by SEQ ID NO: 7, and the HCVR has an amino acid sequence given by SEQ ID NO: 8. In an embodiment, the antibody comprises a light chain (LC) and a heavy chain (HC), wherein the LC has an amino acid sequence given by SEQ ID NO: 9, and the HC has an amino acid sequence given by SEQ ID NO: 10. In an embodiment, th