Anti-TREM1 antibodies and related methods
Inventors
Chan, Christopher • Pal, Aritra • Sriram, Venkataraman • Presta, Leonard G. • LE, Tiep Tu • Liang, Linda
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10836828-B2
Publication Date
2020-11-17
Expiration Date
Abstract
Provided herein are anti-TREM1 antibodies and related methods of making and using anti-TREM1 antibodies. Also provided are methods and compositions for enhancing an immune response and/or for the treatment of an immune-related condition in an individual, e.g., cancer, comprising killing, disabling, or depleting non-stimulatory myeloid cells using an anti-TREM1 antibody or antigen binding fragment thereof.
Core Innovation
The invention relates to isolated anti-human TREM1 antibodies and afucosylated TREM1 antibodies that bind human TREM1 (SEQ ID NO: 1) and are defined by specific variable heavy chain and variable light chain complementarity determining region (CDR) sequences. The antibodies include a variable heavy chain comprising three heavy chain CDRs and a variable light chain comprising three light chain CDRs, with alternative CDR-H3 sequence sets specified.
The invention further describes competitive binding and epitope mapping features for anti-human TREM1 antibodies, including criteria for competition based on reference antibody binding in a competitive binding assay. It identifies epitopes on human TREM1 as non-contiguous epitope residues comprising residues 21–34, 103–109, and 128–136 (SEQ ID NOs 42–44), and describes binding performance and kinetics using dissociation constant KD measured by Biacore/SPR and EC50 binding to human monocytes and human neutrophils by flow cytometry, including reduced binding to neutrophils.
The document also characterizes functional categories of TREM1 antibodies as agonist, antagonistic, depleting, and neutralizing antibodies, and links Fc effector functions to biological activity, including ADCC, CDC, and ADCP with C1q and Fc gamma receptors (FcγR). It further connects TREM1 antibody action to reprogramming non-stimulatory myeloid cells (NSMs) into stimulatory myeloid cells (SDCs), inducing pro-inflammatory cytokines/chemokines and costimulatory molecules such as CD40 and HLA-DR, and includes immune modulation concepts for cancer immunotherapy and diagnostic uses involving disabling and/or depleting NSMs.
The patent additionally describes afucosylated TREM1 antibodies and reports improved Fc-receptor binding profiles and better overall binding properties for cynomolgus TREM1. It also reports receptor occupancy in monocytes and neutrophils and, in human leukocytes, a dose-dependent pro-inflammatory cytokine and chemokine signature upon afucosylation, with examples summarizing combination use of anti-TREM1 with anti-PD-1 and broader findings that TREM1 expression in tumors is associated with myeloid cell populations and anti-tumor inflammatory programs.
Claims Coverage
Two independent claims are identified. Each independent claim defines an isolated antibody that binds human TREM1 (SEQ ID NO: 1) and is specified by particular heavy-chain and light-chain CDR sequence sets, with the distinguishing feature being the CDR-H3 sequence.
Cdr-defined anti-human TREM1 antibody variable heavy chain and light chain
An isolated antibody that binds to human TREM1 (SEQ ID NO: 1), comprising a variable heavy chain sequence with CDR-H1, CDR-H2, and CDR-H3 and a variable light chain sequence with CDR-L1, CDR-L2, and CDR-L3, wherein CDR-H1 comprises SEQ ID NO: 23; CDR-H2 comprises SEQ ID NO: 24; CDR-H3 comprises SEQ ID NO: 33; CDR-L1 comprises SEQ ID NO: 26; CDR-L2 comprises SEQ ID NO: 27; and CDR-L3 comprises SEQ ID NO: 28.
Alternative cdr-defined anti-human TREM1 antibody cdr-h3 sequence
An isolated antibody that binds to human TREM1 (SEQ ID NO: 1), comprising a variable heavy chain sequence with CDR-H1, CDR-H2, and CDR-H3 and a variable light chain sequence with CDR-L1, CDR-L2, and CDR-L3, wherein CDR-H1 comprises the sequence set forth in SEQ ID NO: 23; CDR-H2 comprises the sequence set forth in SEQ ID NO: 24; CDR-H3 comprises the sequence set forth in SEQ ID NO: 32; CDR-L1 comprises the sequence set forth in SEQ ID NO: 26; CDR-L2 comprises the sequence set forth in SEQ ID NO: 27; and CDR-L3 comprises the sequence set forth in SEQ ID NO: 28.
The claim coverage is directed to isolated antibodies that bind human TREM1 (SEQ ID NO: 1) and are defined by specific CDR sequence sets for the variable heavy chain and variable light chain, with the key distinction being the specified CDR-H3 sequence (SEQ ID NO: 33 versus SEQ ID NO: 32).
Stated Advantages
Reprogramming non-stimulatory myeloid cells (NSMs) into stimulatory myeloid cells (SDCs).
Inducing pro-inflammatory cytokines/chemokines.
Inducing costimulatory molecules including CD40 and HLA-DR.
Increasing immune response or disabling/depleting NSMs.
Improved Fc-receptor binding profiles.
Better overall binding properties for cynomolgus TREM1.
Induces a dose-dependent pro-inflammatory cytokine and chemokine signature in human leukocytes upon afucosylation.
Combination anti-TREM1 plus anti-PD-1 supports cytokine induction and tumor efficacy.
Documented Applications
Cancer immunotherapy and diagnostic concepts using TREM1-binding antibodies for increasing immune response or disabling/depleting NSMs.
Immune modulation by linking TREM1 antibody action to reprogramming NSMs into SDCs and inducing pro-inflammatory cytokines/chemokines and costimulatory molecules.
Characterization of afucosylated TREM1 antibodies for receptor occupancy in monocytes and neutrophils.
Induction of pro-inflammatory cytokine and chemokine signatures in human leukocytes upon afucosylation.
Combination treatment with anti-TREM1 and anti-PD-1 to support cytokine induction and tumor efficacy in in vivo tumor models.
Use of TREM1 expression in tumors as a basis for association with myeloid cell populations and anti-tumor inflammatory programs.
Interested in licensing this patent?