Anti-TREM2 antibodies and methods of use thereof
Inventors
Dennis, Mark S. • Duncan, Sherie • Lisaingo, Kathleen • MONROE, KATHRYN M. • Park, Joshua I. • Prorok, Rachel • Shi, Ju • SRIVASTAVA, Ankita • Van Lengerich, Bettina • Walsh, Riley
Assignees
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Publication Number
US-12240902-B2
Publication Date
2025-03-04
Expiration Date
Abstract
In one aspect, antibodies that specifically bind to a human triggering receptor expressed on myeloid cells 2 (TREM2) protein are provided. In some embodiments, the antibody decreases levels of soluble TREM2 (sTREM2). In some embodiments, the antibody enhances TREM2 activity.
Core Innovation
The invention relates to isolated antibodies or antigen-binding fragments that specifically bind human triggering receptor expressed on myeloid cells 2 (TREM2). Binding specificity is defined by CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence patterns expressed with SEQ ID NOs, allowed residue substitutions, and enumerated CDR sequence options. The scope includes antibodies and antigen-binding fragments configured to recognize human TREM2 and an epitope referenced as SEQ ID NO:1.
The described antibodies are characterized as anti-human TREM2 antibodies that bind TREM2 on cells and demonstrate functional activity in assays measuring pSyk signaling activation and NFAT reporter activation. The document connects these antibody effects to TREM2-dependent signaling readouts, including macrophage survival, changes associated with soluble TREM2 shedding, myelin debris phagocytosis, and effects on phagocytosis and myeloid cell function. Epitope recognition is further supported by epitope binning, stalk versus IgV domain agonist bins, and reference to epitope residues and corresponding SEQ ID NOs.
The invention further provides claim-adjacent scope for antibody formats and binding relationships, including variable region identity features, specific VH/VL SEQ ID combinations, epitope competition, binding potency, and cross-reactivity. The document also references cross-reactivity with cynomolgus TREM2, pharmacokinetics and target engagement in mice/humanized TREM2 KI, human sequence optimization for comparable or sufficient affinities, and therapeutic applications for modulating sTREM2 levels in neurodegenerative diseases.
Claims Coverage
The independent claim coverage centers on isolated antibodies or antigen-binding fragments that specifically bind human TREM2, defined by full CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence patterns using SEQ ID NO references and residue constraints. Across the independent claims, the inventive features include fixed CDR patterns with residue options, enumerated CDR sequence sets, and claim scope that also references variable-region identity, specific VH/VL SEQ ID combinations, and pharmaceutical composition and method-of-treatment coverage for listed neurodegenerative diseases.
TREM2-specific antibody defined by full CDR sequence patterns
An isolated antibody or antigen-binding fragment that specifically binds human TREM2, comprising a CDR-H1 sequence (SEQ ID NO:293) with specified allowed residue identities, a CDR-H2 sequence (SEQ ID NO:294) with specified allowed residue identities, a CDR-H3 sequence (SEQ ID NO:295) with specified allowed residue identities, a CDR-L1 sequence (SEQ ID NO:296 or SEQ ID NO:297) with specified allowed residue identities, a CDR-L2 sequence (SEQ ID NO:298) with specified allowed residue identities, and a CDR-L3 sequence (SEQ ID NO:299) with specified allowed residue identities.
Specified CDR sequence set for anti-TREM2 binding
An isolated antibody or antigen-binding fragment that specifically binds human TREM2, comprising a CDR-H1 sequence comprising the sequence of G-Y-ϵ13-F-ϵ15-S-ϵ17-ϵ18-ϵ19-ϵ110 (SEQ ID NO:306) with specified residue-variant options, a CDR-H2 sequence comprising the sequence of Y-I-N-P-Y-S-ϵ27-G-ϵ29-N-Y-N-E-K-F-K-ϵ217 (SEQ ID NO:307) with specified residue-variant options, a CDR-H3 sequence comprising the sequence of ARSSYRYGFDY (SEQ ID NO:46), a CDR-L1 sequence comprising the sequence of KASEDIYNRLA (SEQ ID NO:47), a CDR-L2 sequence comprising the sequence of GATSLET (SEQ ID NO:48), and a CDR-L3 sequence comprising the sequence of Q-Q-ϵ43-W-S-ϵ46-P-W-T (SEQ ID NO:308) with specified residue-variant options.
Enumerated CDR sequence sets for human TREM2-binding antibodies
An isolated antibody or antigen-binding fragment that specifically binds human TREM2, wherein each CDR is selected from a listed set of SEQ ID NOs for CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.
Overall claim coverage centers on TREM2-specific antibodies and antigen-binding fragments whose specificity is defined by SEQ ID-referenced CDR-H1/H2/H3 and CDR-L1/L2/L3 sequence constraints, including fixed patterns with residue options and enumerated sequence sets. The claims also refer to variable-region identity, specific VH/VL SEQ ID combinations, and pharmaceutical composition and treating neurodegenerative disease by modulating TREM2/sTREM2-related effects.
Stated Advantages
Decreases soluble TREM2 (sTREM2).
Enhances TREM2 signaling, including via Syk phosphorylation and NFAT reporter activation.
Provides therapeutic treatment of neurodegenerative diseases by modulating sTREM2 levels.
Shows binding to TREM2 on cells and functional activity in TREM2-dependent assays.
Supports macrophage survival and myelin debris phagocytosis.
Includes cross-reactivity with cynomolgus TREM2, pharmacokinetics, and target engagement in mice/humanized TREM2 KI.
Documented Applications
Therapeutic treatment of neurodegenerative diseases by modulating sTREM2 levels, including disease selections referenced in the dependent claim scope.
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