Invented by Kent B. Thudium, Mark J. Selby, Kyra D. Zens, Mark Yamanaka, Alan J. Korman, Heidi N. LeBlanc, ER Squibb and Sons LLC

The market for human antibodies that bind lymphocyte activation protein-3 (LAG-3), and their uses, is witnessing significant growth and garnering attention from the biopharmaceutical industry. LAG-3 is an immune checkpoint receptor expressed on various immune cells, including T cells, B cells, and natural killer cells. It plays a crucial role in regulating immune responses and has emerged as a promising target for therapeutic interventions in several diseases, particularly cancer. LAG-3 is known to negatively regulate T cell activation and function, acting as a brake on the immune response. By binding to LAG-3, antibodies can block its inhibitory signals and enhance the immune system’s ability to recognize and eliminate cancer cells. This mechanism makes LAG-3 an attractive target for the development of immunotherapies, especially in combination with other checkpoint inhibitors such as PD-1/PD-L1. The market for human antibodies that bind LAG-3 is driven by the increasing prevalence of cancer and the growing demand for effective immunotherapies. According to the World Health Organization (WHO), cancer is one of the leading causes of death worldwide, with approximately 10 million deaths reported in 2020 alone. Traditional treatment modalities, such as chemotherapy and radiation therapy, have limitations in terms of efficacy and potential side effects. Therefore, there is a pressing need for novel therapeutic approaches that can harness the power of the immune system to fight cancer. Several biopharmaceutical companies are actively engaged in the development of LAG-3-targeted antibodies. These companies are investing heavily in research and development to identify and optimize lead candidates that can effectively bind LAG-3 and modulate immune responses. Additionally, collaborations and partnerships between academic institutions, pharmaceutical companies, and biotechnology firms are further fueling the growth of this market. The potential applications of LAG-3-targeted antibodies extend beyond cancer therapy. LAG-3 has also been implicated in autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, where aberrant immune responses contribute to tissue damage. By blocking LAG-3, antibodies can potentially restore immune balance and alleviate disease symptoms. Furthermore, LAG-3-targeted antibodies are being explored as a means to enhance the efficacy of vaccines by boosting immune responses. The market for human antibodies that bind LAG-3 is expected to witness substantial growth in the coming years. Factors such as increasing research and development activities, rising investments in biopharmaceutical companies, and the growing understanding of LAG-3’s role in immune regulation are driving this growth. Moreover, the success of approved immune checkpoint inhibitors targeting other receptors, such as PD-1 and CTLA-4, has paved the way for the development of LAG-3-targeted therapies. However, challenges remain in the development of LAG-3-targeted antibodies. One of the major hurdles is identifying the optimal combination therapies that can maximize the clinical benefits. Additionally, the complex interplay between different immune checkpoints and their potential overlapping functions necessitates a thorough understanding of the underlying biology to design effective therapeutic strategies. In conclusion, the market for human antibodies that bind LAG-3 is poised for significant growth due to the increasing demand for novel immunotherapies in cancer and autoimmune diseases. The potential of LAG-3 as a therapeutic target, combined with advancements in antibody engineering and drug development, holds promise for improving patient outcomes and revolutionizing the field of immune-based therapies. Continued research and collaboration among stakeholders will be crucial in unlocking the full potential of LAG-3-targeted antibodies and harnessing the power of the immune system to combat diseases.

The ER Squibb and Sons LLC invention works as follows

The present disclosure contains isolated monoclonal monoclonal antibody that binds to LAG-3 with high affinity. It is particularly useful for monoclonal human antibodies. The antibodies should bind to LAG-3 from human beings. The antibodies may bind LAG-3 to both monkey and human LAG-3 in certain embodiments. However, they do not bind LAG-3 to mice. Anti-LAG-3 antibodies are provided by the invention that inhibit LAG-3 binding to WIC Class II molecules. They can also stimulate antigen-specific T cells responses. The invention also provides nucleic acid molecules that encode the antibodies, expression vectors and host cells for the invention. The invention also provides bispecific molecules, immunoconjugates and pharmaceutical compositions containing the antibodies. This disclosure provides methods for detecting LAG-3 and methods for treating immune reactions using anti-LAG-3 antibodies of the invention. Combination therapy is where an anti-LAG-3 anti- antibody is administered in combination with at least one other immunostimulatory antibody.

Background for Human antibodies that bind lymphocyte activation protein-3 (LAG-3), and their uses

LAG-3, also known as CD223, is a member the immunoglobulin supergene and structurally and genetically related with CD4. LAG-3 does not express on resting peripheral blood lymphocytes, but it is expressed on activated T and NK cells. LAG-3, a membrane protein encoded in a gene on the distal end of the short arm chromosome 12, close to the CD4 gene suggests that LAG-3 may have evolved by gene duplication (Triebel and al. (1990) J. Exp. Med. 171:1393-1405).

LAG-3 is similar to CD4, but unlike CD4, it has been shown to interact with MHC Class II molecules. However, LAG-3 does NOT interact with the human immune deficiency virus (HIV) gp120 protein (Baixeras and al. (1992) J. Exp. Med. 176:327-337). Huard et. al. demonstrated that LAG-3 can be bound directly to MHC class II cells by using a soluble LAG-3 immunoglobulin-fusion protein (sLAG-3Ig). (1996) Eur. J. Immunol. 26:1180-1186).

In in vitro studies on antigen-specific responses to T cells, adding anti-LAG-3 antibody led to an increase in T cell proliferation and expression of activation markers such as CD25. It also increased the concentration of cytokines like interferon-gamma, interleukin-4 and other cytokines, indicating that the LAG/MHC interaction is involved in the down-regulation of antigen dependent stimulation of CD4+ lymphocytes. (1994) Eur. J. Immunol. 24:3216-3221). The intra-cytoplasmic LAG-3 region has been shown to interact with LAP (a protein thought to be involved in signal transduction molecules that are responsible for the downregulation the CD3/TCR activated pathway) (Iouzalen and al. (2001) Eur. J. Immunol. 31:2885-2891). 31:2885-2891). (2004) Immunity 21.503-513. Further, LAG-3 was shown to negatively affect T cell homeostasis in T cell dependent and independent mechanisms by regulatory T cells (Workman, C. J., and Vignali D. A.). (2005) J. Immunol. 174:688-695).

LAG-3 has also been shown to be immunostimulatory in certain situations. LAG-3-transfected tumor cells were transplanted into syngeneic mice and showed significant growth reductions or complete regression compared to untransfected cells. This suggests that LAG-3 expression on tumor cells stimulated an antitumor response via activating antigen presenting cells via MHC Class II molecules (Prigent et. al. (1999) Eur. J. Immunol. 29:3867-3876). In addition, the soluble LAG-3 Ig protein fusion protein stimulates both humoral as well as cellular immune responses in mice when given with an antigen (El Mir and Triebel, 2000 J. Immunol. 164:5583-5589). In vitro generation and maintenance of type I tumor-specific immunity has been enhanced by soluble human LAG-3Ig (Casati, et al. (2006) Cancer Res. 66:4450-4460). Triebel (2003) Trends Immunol. 24:619-622. A number of additional agents that can modulate the activity of LAG-3 may be of interest in light of the above.

The present disclosure contains isolated monoclonal monoclonal antibody, particularly human monoclonal antibody, that specifically bind LAG-3. It also has desirable functional properties. These properties include high affinity binding, binding to LAG-3 in human, monkey, and rhesus monkey LAG-3 (e.g. cynomolgus LAG-3 and/or rhesus LAG-3), the ability to inhibit LAG-3 binding to major histocompatibility Class II molecules, and/or the ability stimulate antigen-specific T cells responses. The invention’s antibodies can be used to detect LAG-3 proteins or stimulate antigen-specific cell responses in tumor-bearing subjects or virus-bearing subjects.

In one aspect, this invention pertains to an isolate human monoclonal antibody or an antigen binding portion thereof wherein the antibody binds to human LAG-3 and exhibits at minimum one of these properties:

(a) binds the monkey LAG-3

(b), does not bind the mouse LAG-3

(c), inhibits the binding of LAG-3 with major histocompatibility class II molecules (MHC); and

(d), stimulates an immunological response.

Preferably the antibody exhibits two or more of these properties: (a),(b), (c), and (d). The antibody is even more preferably exhibiting at least three properties (a),(b), (c), and (d). “Even more preferably, it is the case that the antibody possesses all four properties (a), b), c), and d”.

In an alternative aspect, the invention refers to an isolated monoclonal antibody from a human being, or the antigen binding portion thereof. The antibody crosses-competes with a reference antibody to bind to human LAG-3.

(a), a heavy-chain variable region containing the amino acids sequence of SEQID NO: 37, and a lighter-chain variable region containing the amino acids sequence of SEQID NO: 43

(b), a heavy-chain variable region containing the amino acids sequence of SEQID NO: 38, and a lighter-chain variable region containing the amino acids sequence of SEQID NO: 44.

(c), a heavy-chain variable region containing the amino acids sequence of SEQID NO: 39, and a lighter-chain variable region containing the amino acids sequence of SEQID NO: 45.

(d), a heavy-chain variable region containing the amino acids sequence of SEQID NO: 40, and a lighter-chain variable region containing the amino acids sequence of SEQID NO: 46

(e), a heavy-chain variable region containing the amino acids sequence of SEQID NO: 41, and a lighter-chain variable region containing the amino acids sequence of SEQID NO: 47

(f), a heavy-chain variable region containing the amino acids sequence of SEQID NO: 42, and a lighter-chain variable region containing the amino acids sequence of the SEQID NO: 48.

In a preferred embodiment, a reference antibody includes a heavy-chain variable region that contains the amino acids sequence of SEQID NO: 37 and a lighter chain variable region that comprises the amino acid sequences of SEQID NO: 43. A preferred embodiment of the reference antibody includes a heavy-chain variable region that contains the amino acids sequence of SEQID NO: 38 and a lighter chain variable region that contains the amino sequence of SEQ ID NO: 44. A preferred embodiment of the reference antibody includes a heavy-chain variable region that contains the amino acids sequence of SEQID NO: 39, and a light-chain variable region that comprises the amino sequence of SEQ ID NO: 45. A preferred embodiment of the reference antibody includes a heavy-chain variable region that contains the amino acids sequence of SEQID NO: 40, and a light-chain variable region that contains the amino sequence of SEQ ID NO 46. A preferred embodiment of the reference antibody includes a heavy-chain variable region that contains the amino sequence of SEQID NO: 41, and a light-chain variable region that comprises the amino sequence of SEQ ID NO: 47. A preferred embodiment of the reference antibody includes a heavy-chain variable region that contains the amino sequence of SEQID NO: 42, and a light-chain variable region that comprises the amino sequence of SEQ ID NO: 48.

Another aspect of the invention is an isolated monoclonal anti-body, or an antigen binding portion thereof. It comprises a heavy chain variable area that is either the product or derived from a VH 3-20, VH 4-34, VH 1-23, or VH 3-33 genes. The antibody specifically binds to human LAG-3. Another aspect of the invention is an isolated monoclonal anti-body, or an antigen binding portion thereof. It comprises a light chain variable area that is either the product or derived form a VK L18 human gene, a VK L6 human gene or a VK A27 human gene. The antibody specifically binds to human LAG-3. Preferably, the invention is an isolated monoclonal antibody or an antigen binding portion of it.

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