Invented by Michel Streuli, Venkataraman Sriram, Aritra Pal, Leonard G. Presta, Pionyr Immunotherapeutics Inc

The market for Anti-TREM2 antibodies, and related methods In recent years, there has been a growing interest in the development of therapies targeting neurodegenerative diseases. One particular area of focus is the role of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) protein in the progression of these diseases. As a result, the market for Anti-TREM2 antibodies and related methods has been gaining traction. TREM2 is a receptor protein primarily expressed on the surface of microglia, the immune cells of the central nervous system. It plays a crucial role in regulating the inflammatory response and phagocytosis, the process by which microglia clear cellular debris and pathogens. Dysfunction of TREM2 has been implicated in various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. The development of Anti-TREM2 antibodies aims to modulate the activity of TREM2 and potentially slow down the progression of these diseases. These antibodies can be designed to either enhance or inhibit the function of TREM2, depending on the specific therapeutic strategy. For instance, enhancing TREM2 activity may promote the clearance of toxic protein aggregates, while inhibiting TREM2 activity may reduce the inflammatory response associated with neurodegeneration. The market for Anti-TREM2 antibodies is expected to witness significant growth in the coming years. This can be attributed to several factors. Firstly, the prevalence of neurodegenerative diseases is on the rise globally, creating a substantial unmet medical need. According to the World Health Organization, nearly 50 million people worldwide are affected by dementia, with Alzheimer’s disease being the most common form. This increasing patient population is driving the demand for effective therapies. Secondly, the growing understanding of the role of TREM2 in neurodegenerative diseases has fueled research and development efforts in this field. Numerous pharmaceutical and biotechnology companies are actively engaged in developing Anti-TREM2 antibodies and related methods. These companies are investing heavily in preclinical and clinical studies to evaluate the safety and efficacy of these therapies. Furthermore, advancements in technology and drug discovery techniques have facilitated the identification and development of Anti-TREM2 antibodies. The use of high-throughput screening methods, such as phage display and hybridoma technology, has enabled the identification of antibodies with high specificity and affinity for TREM2. Additionally, the availability of transgenic animal models that mimic human neurodegenerative diseases has facilitated the evaluation of these antibodies in preclinical studies. However, the market for Anti-TREM2 antibodies also faces certain challenges. One of the major hurdles is the complexity of neurodegenerative diseases, which often involve multiple pathological mechanisms. Developing a therapy that effectively targets TREM2 while considering other disease-related factors is a significant challenge. Additionally, the high cost associated with the development and production of antibodies may limit their accessibility to patients. In conclusion, the market for Anti-TREM2 antibodies and related methods is witnessing significant growth due to the increasing prevalence of neurodegenerative diseases and the growing understanding of the role of TREM2 in these conditions. The development of effective therapies targeting TREM2 holds great promise in slowing down the progression of these devastating diseases. However, further research and clinical trials are needed to validate the safety and efficacy of these antibodies, and to overcome the challenges associated with their development.

The Pionyr Immunotherapeutics Inc invention works as follows

Anti-TREM2 antibody and related methods for making and using anti TREM2 antibody are described here. The invention also includes methods and compositions that enhance an immune response or treat an immune-related disease in a person, such as cancer. These include killing, disabling or depleting myeloid non-stimulating cells with an anti-TREM2 antigen-binding fragment.

Background for Anti-TREM2 antibodies, and related methods

Immunity is important in the prevention of tumor growth. The lesion can become a complex microenvironment, and even though T-cells are recruited, the mass is not always controlled. Understanding the balance between tumour elimination and tumor evasion may depend on an understanding of the different roles myeloid cell play in the tumor environment.

Myeloid cells are prominent in the tumor microenvironment. They include macrophages and neutrophils. It has been known for a long time that intra-tumoral populations of myeloid cells were non-stimulatory and suppressive. However, more recently, it was realized that not all myeloid tumor-infiltrating cells are the same.

In normal tissues, these myeloid cell types are crucial for the proper functioning of innate and adaptive immune systems and for wound healing. In the context of cancer, an excess of macrophages is often observed as well as dysfunctional or skewed cell populations. When defined as a single aggregate population, such as by CD68 or CD163, “macrophage” is a term that can be used. Infiltration correlates with poorer outcomes across multiple tumor types in patients (de Visser, Cancer Immunol Immunother 2008; 57; 1531-9; Hanada et. al., Int J Urol, 2000; 7; 263-9); Yao et. al. Clin Cancer Res, 520, 2001; 7:4021-6); (Ruffell et al., PNAS, 523 2012; 109:2791-801)). The similarity between macrophages, dendritics cells and tumor microenvironment complicates the sub-set of macrophages in the tumor environment. This is a problem for tumor biology. One morphologic criterion that has been used to distinguish macrophages from dendritic cell is a spikey or dendritic morphology. Some groups try to differentiate based on genetic and cell surface markers.

There are many antigen-presenting cells within tumors and T-cells have the ability to differentiate between them.” Understanding the features of APCs that are cognate to T cells is important because they are major drivers of tumor immunity. Myeloid cells play a major role in presenting antigens derived from tumors to T cells and maintaining them in an active state. The antigen is presented within the tumor and may influence the function of tumor cytotoxic lymphocytes (CTLs). Antigen-presenting cells (APCs) are important in antigen-specific immunity and tumor cell death. Understanding the differences between these myeloid cells, which are important T-cell-interacting partner and antigen-presenting cell for incoming tumor reactive cytotoxic T lymphocytes can guide therapeutic avenues.

Related Patent Applications include: PCT/US2015/052682 filed Sep. 28 2015; and PCT/US2016/054104, which were filed Sep. 28 2016. Each of these is hereby incorporated herein by reference in their entirety for all purposes.

All patents, applications for patents, publications, documents and articles are incorporated by reference herein in their entirety.

The isolated antibody described herein binds human TREM2 and competes with the 37017 (SEQ NOs 31 and 32) antibody for binding mouse TREM2(SEQ NO:17).

In certain embodiments, the antibodies comprise a CDRH1 comprising a sequence as set forth by SEQID NO: 9, a CDRH2 comprising a sequence as set forth by SEQID NO: 10, and a CDRH3 comprising a sequence as set forth by SEQID NO: 11. A CDRL1 comprises the sequence that is set forth by SEQID NO: 12, a CDRL2 comprises the sequence that is set forth by SEQID NO: 13,

In certain embodiments, the antigen is afucosylated. It contains the VH and VL sequences shown in SEQ NO: 1, and the active human IgG1Fc region.

In some embodiments, an antibody may contain all three heavy chain CDRs from the sequence SEQ NO:7 as well as all three light chain CDRs from the sequence SEQ NO:8.

In certain embodiments, the antibodies comprise an A to T replacement at position 97 in the sequence SEQID NO:7 and a R to K substitution at the position 98 in the sequence SEQID NO:7.

In some embodiments the antibody contains the VH sequence as shown in SEQ NO: 1, 3 or 5.

The antibody may contain the VH sequence in SEQ NO: 1, 3 or 5, and the VL in SEQ NO: 2, 4 or 6.

In some embodiments the antibody contains the VH sequence as shown in SEQID NO: 1.

In some embodiments the antibody contains the VH sequence in SEQ NO: 1 as well as the VL sequence in SEQ NO: 2.

In some embodiments the antibody is 37012.

In some embodiments the antibody contains the heavy chain shown in SEQID NO: 25 and light chain shown in SEQID NO: 26.

The invention describes an isolated human Fc antibody which competes with 37017 (SEQID NOs 31 and 32) for binding to mouse TREM2(SEQID NO:17), and contains an active human Fc area.

In some cases, the antibodies are humanized or chimeric.

In some cases, the antibodies are humanized.

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