Invented by Scott Koenig, Leslie S. Johnson, Chia-Ying Kao Lam, Liqin Liu, Jeffrey Lee Nordstrom, Barton F. Haynes, Guido Ferrari, Macrogenics Inc, Duke University

The market for bispecific molecules that are immune-reactive with effector cells that have an activating receptor, and antigens expressed is rapidly growing in the field of immunotherapy. These molecules hold immense potential in the treatment of various diseases, including cancer and autoimmune disorders. Bispecific molecules are designed to simultaneously bind to two different targets, typically an activating receptor on immune cells and a specific antigen expressed on diseased cells. This unique characteristic allows them to bridge the gap between immune cells and target cells, leading to enhanced immune response and targeted cell killing. In the context of cancer treatment, bispecific molecules can redirect immune cells, such as T cells or natural killer (NK) cells, towards tumor cells expressing specific antigens. By binding to both the immune cell receptor and the tumor antigen, these molecules activate the immune cells and trigger their cytotoxic activity against cancer cells. This approach has shown promising results in clinical trials, with some bispecific molecules demonstrating remarkable efficacy in treating certain types of cancer. One of the key advantages of bispecific molecules is their ability to engage multiple immune cell types simultaneously. This feature allows for a more robust and coordinated immune response against the target cells. For example, bispecific T cell engagers (BiTEs) can simultaneously engage T cells and tumor cells, leading to the formation of an immunological synapse and subsequent T cell-mediated killing of the tumor cells. Similarly, bispecific antibodies can engage both NK cells and tumor cells, resulting in NK cell-mediated cytotoxicity. The market for bispecific molecules is expected to witness significant growth in the coming years. The increasing prevalence of cancer and autoimmune disorders, coupled with the need for more effective and targeted therapies, is driving the demand for innovative immunotherapies. Bispecific molecules offer a promising solution by leveraging the power of the immune system to selectively eliminate diseased cells while sparing healthy tissues. Several pharmaceutical companies and biotechnology firms are actively engaged in the development of bispecific molecules. These companies are investing heavily in research and development to identify novel targets, optimize molecule design, and conduct clinical trials to evaluate their safety and efficacy. The market is witnessing collaborations and partnerships between industry players to combine their expertise and resources for accelerated development and commercialization of bispecific molecules. However, there are still challenges to overcome in the development of bispecific molecules. One of the major hurdles is the complexity of molecule design and manufacturing. Bispecific molecules often require intricate engineering to ensure proper binding affinity and specificity to both targets. Additionally, the production of these molecules at a large scale can be technically challenging and costly. Regulatory considerations also play a crucial role in the market for bispecific molecules. As these molecules are relatively new and innovative, regulatory agencies are continuously evolving their guidelines for their development and approval. Companies need to navigate these regulatory landscapes to ensure timely market entry and commercial success. In conclusion, the market for bispecific molecules that are immune-reactive with effector cells that have an activating receptor, and antigens expressed is witnessing rapid growth. These molecules hold great promise in the field of immunotherapy, offering targeted and potent therapies for cancer and autoimmune disorders. With ongoing research and development efforts, along with collaborations and partnerships, the market is expected to expand further, providing new treatment options for patients in need.

The Macrogenics Inc, Duke University invention works as follows

The present invention is a bispecific molecule that can localize an immune effector that expresses a receptor activating to a virally-infected cell to facilitate the killing of that virally-infected cell. In a preferred embodiment of the invention, localization of the immune effector cells is achieved by using bispecific molecule that are immunoreactive to an activating receptor and an antigen expressed on a cell that has been infected by a virus, wherein the antigen on the infected cell is detectable at a higher level than that at which it is detected by the bispecific molecule, and the use of these bispecific moleculs in the treatment latent viral infection.

Background for Bispecific molecules that are immune-reactive with effector cells that have an activating receptor, and antigens expressed by infected cells by viruses and their uses

Field of Invention

The present invention is a bispecific molecule that can localize an immune effector that expresses a receptor activator to a virally-infected cell to facilitate the killing of that virally-infected cell. In a preferred embodiment of the invention, localization is achieved using bispecific molecules immunoreactive to both an activating receptor expressed by an immune effector and an epitope of a viral antigen expressed on a cell. The present invention also relates to the use such bispecific molecule in the treatment latent viral infection, persistent viral infection, inactive viral infections as well as the use such bispecific molecule in methods for killing cells expressing viral proteins or cells containing viral genomes. The invention is particularly concerned with bispecific molecule that binds to (1) an antigen expressed on a cell that has been infected, at a higher level than that at which it is detected by the bispecific molecule, and (2) a receptor epitope on an activating cell of an immune cell.

Description of Related Art.

I. “Viral Infectious Disease

The last few decades have seen a revival of interest in the therapeutic potential of antibodies, and antibodies have become one of the leading classes of biotechnology-derived drugs (Chan, C. E. et al. (2009) “The Use Of Antibodies in the Treatment Of Infectious Disorders”, Singapore Med. J. 50(7):663-666). Nearly 200 antibodies-based drugs are approved or under development.

Such drugs are particularly promising for the treatment and prevention of infectious diseases. This is especially true for viral infections. Many pathogens have demonstrated a marked ability to gain resistance to conventional antimicrobial drugs (e.g., methicillin-resistant Staphylococcus aureus, extreme drug-resistant Mycobacterium tuberculosis and antimicrobial resistant Plasmodium falciparum). HIV, influenza virus and other pathogens are also resistant to conventional antimicrobial drugs. The traditional drugs are not able to treat the disease in a satisfactory manner (see Beigel, J. Current and Future Antiviral Treatment Of Severe Avian Influenza And Seasonal Influenza? Antiviral Res. 78(1):91-102). These drugs also have significant side effects. Antibodies are highly attractive therapeutic agents because they have two distinct properties. Since antibodies are native endogenous proteins, they have low toxicity. They are highly specific, which allows them to be targeted at infected cells.

However, current immunotherapy has some drawbacks” (Chan, C. E. The Use Of Antibodies in the Treatment Of Infectious Disorders? Singapore Med. J. 50(7):663-666). T-cell mediated adaptive immunity is often associated with the clearance of viral infections. CD8+T cells kill virally-infected cell, reducing viral load and preventing viral reproduction. In addition to neutralizing viruses, antibodies also promote the death of infected cell surfaces expressing viral proteins. This is done by activating natural killer cells (NK), which mediate ADCC. While antibodies have been shown in vitro to be capable of neutralizing many viral pathogens, it is not clear how antibody-mediated immune system can help achieve viral clearance. Neutralizing therapeutic antibodies, therefore, are not administered to achieve viral clearance but to suppress viral replication, viremia, and allow the host immune system to develop an efficient response. Studies have shown, in this regard, that the ability of antibodies to reduce viral loads correlates with the persistency of the administered antibody, and that viral antigens levels eventually recover once antibody levels had declined after the cessation therapy (Galun E. et. al. Clinical Evaluation (Phase 1) Of A Combination Of Human Monoclonal antibodies To HBV: Antiviral and Safety Properties? Hepatology 35:673-679; Heijtink, R. A. et al. Administration Of A Human Monoclonal (TUVIRUMAB), To Chronic Hepatitis B Pre-Treated with Lamivudine Patients: Monitoring Of Serum TUVIRUMAB in Immune Complexes (2001). J. Med. Virol. 64:427-434). Studies with HIV also show that regular treatment of therapeutic antibodies can lead to escape mutants. (Chan, C. E., et al. (2009) “The Use Of Antibodies in the Treatment Of Infectious Disorders” Singapore Med. J. 50(7):663-666). In one study, the combination of three broadly-neutralizing HIV antibodies given over a 12-week period was able to delay viral rebound after cessation of treatment. The viral levels recovered eventually despite the continued use of all three anti-HIV antibodies. However, one of the antibodies was more resistant than the other two (Trkola A. and al. (2005) “Delay of HIV-1 Rebound after Cessation of Antiretroviral Treatment Through Passive Transmission Of Human NeutralizingAntibodies” Nat. Med. 11:615-622).

II. Immune System Activation

CD4+ lymphocytes are essential organizers of mammalian immunity and autoimmune response (Dong, C. (2003) “Immune Regulation By Novel Costimulatory Molecules” Immunolog. Res. 28(1):39-48). It has been shown that the activation of CD4+ Helper T-cells is mediated by co-stimulatory interaction between Antigen Presenting cells and naive CD4+ lymphocytes. Viglietta, V. and al. (2007) ?Modulating Co-Stimulation,? Neurotherapeutics 4:666-675; Korman, A. J. et al. Checkpoint Blockade In Cancer Immunotherapy? Adv. Immunol. 90:297-339). The first interaction requires that an Antigen Presenting Cell display the target antigen bound with the cell’s Major Histocompatibility Complex so it can bind the T-cell receptor (?TCR?) A naive, CD4+ T lymphocyte must have a ligand that binds to the CD28 receptor of the CD4+ lymphocyte. In the second interaction, the ligand from the Antigen Presenting Cell binds to the CD28 receptor on the CD4+ lymphocyte (Dong C., et al. (2003) “Immune Regulation By Novel Costimulatory Molecules”,? Immunolog. Res. 28(1):39-48; Lindley, P. S. et al. The Clinical Utility of Inhibiting CD28 Mediated Costimulation? Immunol. Rev. 229:307-321). After receiving both stimulatory signals, CD4+ helper cells can respond to cytokines such as Interleukin-2 or Interleukin-12 to develop into T1 cells. Such cells produce interferon-gamma (IFN-?) These cells produce interferon-gamma (IFN-?) TNF-? ), which elicit inflammatory responses in target cells that express the target antigen. The B-cells are also activated and proliferated, leading to antibody production that is specific for the antigen. (Bernard A., et al. (2005) “T and B Cell Co-operation: A Dance of Life and Death”, Transplantation, 79(S8-S11). The absence of both costimulatory signals when TCR engagement occurs, T cells enter into a functionally non-responsive state (Khawli L. A. and al. (2008) “Cytokine and Chemokine Fusion Proteins for Immunotherapy of Solid Cancers”, Exper. Pharmacol. 181:291-328). In pathological states, Th1-cells are key players in various organ-specific autoimmune disorders, such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. (2003) “Immune Regulation By Novel Costimulatory Molecules” Immunolog. Res. 28(1):39-48).

III. Therapeutic Antibodies

Aside from their well-known diagnostic uses, antibodies have also been shown to be beneficial as therapeutic agents. In recent years, immunotherapy (the use of antibodies as therapeutic agents) has been used to treat infectious diseases. Monoclonal antibody treatment for infection is passive immunotherapy (see, for example, Ian Gust and A.O. (Epub 2012 February 21) “Role of Passive Immunotherapies in Managing Infectious outbreaks” Biologicals 40(3):196-199; Wang, D. et al. Palivizumab for Immunoprophylaxis of Respiratory Synytial Virus Bronchiolitis in High-Risk Children and Infants: A Systematic Analysis And Additional Economic Modeling Of Subgroups Analyses (2011) Health Technol. Assess. 15(5):iii-iv, 1-124; Rosenberg, H. F. et al. (2012) ?Inflammatory Responses To Respiratory Syncytial Virus (RSV) Infection And The Development Of Immunomodulatory Pharmacotherapeutics,? Curr. Med. Chem. 19(10):1424-1431). These antibodies may have intrinsic biological activity by binding directly to infectious agents, such as viruses, bacteria, and fungi. These antibodies can also bind to cells infected by such agents, which express agent-specific antigens. These agents may be used alone or in combination with other antibacterial agents (e.g. antibiotics, antiinflammatory agents, antipyretic agents etc.). Palivizumab is approved to treat respiratory syncytial viral (RSV), bronchiolitis. Tefibazumab in clinical trials will be used for S. aureus infections. As an alternative, antibodies can also be used to create antibody conjugates. These are compounds in which the antigen is bound to a toxin and the toxin is directed to the cancer by binding specifically to it. Gemtuzumab is an example for an antibody conjugate that has been approved to treat leukemia.

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An ideal diagnostic and/or therapeutic antibody would be specific to an antigen that is present on infected cell, but absent or only present at low levels on normal tissue. It would be beneficial to discover, characterize, and isolate a novel antigen-binding antibody that can bind to infected cells and is associated with an infectious and viral disease. The antibody will have biological activity and can be used to activate the immune response in order to treat the disease. The antibody can be used as a therapy alone, in conjunction with other treatments, or to prepare immunoconjugates that are linked to toxic agents. “An antibody with similar specificity, but low or no biological activities when administered alone, could also be useful. An antibody could be used in preparation of an immunoconjugate containing a radioisotope or toxin or a liposome that contains a chemotherapeutic drug or a chemotherapeutic.

The discovery and characterization novel antibodies that can mediate, and in particular enhance the activation of immune cells against infected (and particularly virally infected) cells associated with a wide variety of viral diseases would be desirable.

Despite previous advances, there is still a need for compositions that can bind to infected cells and facilitate or mediate an immune response. A need also remains for compositions that can detect such virally infected cells. This invention aims to identify these compositions. Another object is to develop novel compounds that can be used in the detection and identification of antigens on the surface virally-infected cell surfaces.

The present invention, as described below in detail, relates to bispecific molecule that binds to 1) an epitope on an activating receptor for an immune effector and 2) an antigen epitope expressed by a virally infected cell expressing the antigen. Such bispecific molecule is capable of mediating and, more preferably, enhancing the activation and targeting the immune effectors to the virally infected cells that express the epitope, such that the activated effectors kill

The present invention is a bispecific molecule that can localize an immune effector that expresses a receptor activator to a virally-infected cell to facilitate the killing of that virally-infected cell. In a preferred embodiment of the invention, localization is achieved using bispecific molecules immunoreactive to both an activating receptor expressed by an immune effector and an epitope of a viral antigen expressed on a cell. The present invention also relates to the use such bispecific molecule in the treatment latent viral infection, persistent viral infection, inactive viral infections as well as the use such bispecific molecule in methods for killing cells expressing viral proteins or cells containing viral genomes. The invention is particularly concerned with bispecific molecule that binds to (1) an antigen expressed on a cell that has been infected, at a higher level than that at which it is detected by the bispecific molecule, and (2) a receptor epitope on an activating cell of an immune cell.

In particular, the invention relates to a bispecific molecular comprising:

The invention also relates to the embodiment of a bispecific molecule in which the first epitope binding domain binds a receptor activating the effector cells.

The invention also relates to any of the bispecific molecules described above, wherein an effector cell can be a T cell, CD4+T-cell or CD8+T-cell; a natural killer, macrophage, dendritic, granulocytes, or granulocytes.

The invention also concerns any of those bispecific molecules described above, wherein virus is Epstein Barr virus, herpes virus type 1, herpes virus type 2, human immunodeficiency, hepatitis B, hepatitis C, human papilloma, or influenza virus.

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