Invented by Chien-Hsing Chang, David M. Goldenberg, Edmund A. Rossi, Diane Rossi, Hans J. Hansen, IBC Pharmaceuticals Inc

The market for combination therapy to induce an immune response against disease is rapidly growing as researchers and pharmaceutical companies recognize the potential of this approach in treating various diseases. Combination therapy involves the use of multiple drugs or treatment modalities to enhance the immune system’s ability to fight against diseases such as cancer, autoimmune disorders, and infectious diseases. One of the key advantages of combination therapy is its ability to target multiple pathways or mechanisms involved in disease progression. By using different drugs or treatment modalities that work synergistically, combination therapy can effectively enhance the immune response against diseases that may be resistant to single-agent therapies. This approach has shown promising results in clinical trials, leading to improved patient outcomes and survival rates. In the field of cancer treatment, combination therapy has gained significant attention. Traditional cancer treatments such as chemotherapy and radiation therapy can be highly toxic and have limited efficacy, often leading to the development of drug resistance. By combining these treatments with immunotherapy, which harnesses the power of the immune system to target cancer cells, researchers have observed enhanced tumor regression and improved patient responses. Furthermore, combination therapy can also address the challenges posed by tumor heterogeneity, where cancer cells within a tumor can have different genetic mutations and characteristics. By targeting multiple pathways simultaneously, combination therapy can effectively eliminate cancer cells with different vulnerabilities, reducing the likelihood of treatment resistance and disease recurrence. In addition to cancer, combination therapy is also being explored for the treatment of autoimmune disorders such as rheumatoid arthritis, multiple sclerosis, and lupus. These diseases arise from an overactive immune response, where the immune system mistakenly attacks healthy tissues. By combining immunosuppressive drugs with immune-modulating agents, researchers aim to restore the balance of the immune system and alleviate disease symptoms. In the context of infectious diseases, combination therapy can be used to enhance the immune response against pathogens such as viruses and bacteria. By combining antiviral or antibacterial drugs with immune-stimulating agents, researchers can boost the immune system’s ability to recognize and eliminate the invading pathogens. This approach has shown promise in the treatment of viral infections such as HIV and hepatitis C. The market for combination therapy is expected to grow significantly in the coming years, driven by the increasing prevalence of diseases that are resistant to single-agent therapies and the growing understanding of the immune system’s role in disease progression. Pharmaceutical companies are investing heavily in research and development to identify novel drug combinations and treatment modalities that can effectively induce an immune response against diseases. However, there are challenges that need to be addressed in the development and commercialization of combination therapies. These include identifying the optimal drug combinations, determining the appropriate dosing regimens, and managing potential side effects and drug interactions. Additionally, the high cost of combination therapies may pose a barrier to their widespread adoption, particularly in resource-limited settings. In conclusion, the market for combination therapy to induce an immune response against disease is expanding rapidly, driven by the potential of this approach to improve patient outcomes and address the limitations of single-agent therapies. With ongoing research and development efforts, combination therapy holds great promise in revolutionizing the treatment of various diseases, offering new hope for patients worldwide.

The IBC Pharmaceuticals Inc invention works as follows

The present invention relates to compositions and methods for using bispecific antibodies that contain at least one site of binding for Trop-2 (EGP-1), and at least another site of binding for CD3. Bispecific antibodies can be used to induce an immune response in a tumor expressing Trop-2, such as a cancer of the esophagus or pancreas. They may also be administered with other therapeutic agents, including interferons (preferably interferon-? Methods may include administering the bispecific antibodies alone or in combination with other therapeutic agents, such as interferons, antibody-drug conjugates or interferon-? The bispecific antibody can be administered alone or with other therapeutic agents such as interferons (preferably interferon-? The bispecific antibodies can target effector T-cells, NK cells or monocytes and neutrophils in order to induce leukocyte mediated cytotoxicity against Trop-2+ cancerous cells. “The cytotoxic response is enhanced when interferon and checkpoint inhibitor antibodies are administered together with ADCs or ADCs.

Background for Combination therapy to induce immune response against disease

There are a number of methods for producing bispecific antibodies (see, e.g. U.S. Pat. No. 7,405,320). The quadroma method can produce bispecific antibodies by fusing two hybridomas that each produce a monoclonal antigen-specific antibody (Milstein & Cuello, Nature 1983, 305:537-554). The hybridomas can synthesize two different heavy chains and light chains. These chains can then randomly associate to produce a population of 10 different antibodies, of which one, or a small number, is bispecific. The total number of antibody molecules will only be one bispecific molecule. This must be separated from other forms. “Fused hybridomas can be less stable genetically than their parent hybridomas. This makes the creation of a production line more difficult.

The other method of producing bispecific antibodies is to use heterobifunctional linkers to chemically attach two monoclonal antibody, so that the hybrid conjugate produced will bind to different targets. (Staerz et al. Nature 1985; 314:628-631; Perez, et al. Nature 1985, 316:354-356. This method produces bispecific antibodies that are heteroconjugates, essentially two IgG molecules. They diffuse slowly into tissue and are quickly removed from circulation. The hybrid structure can be obtained by reducing each monoclonal antibody to its respective half molecule, and then mixing them and allowing the reoxidation to occur (Staerz & Bevan). Proc Natl Acad Sci USA 1986; 83:1453-1457). A second approach is to cross-link two or more purified Fab? Using appropriate linkers, a second approach involves chemically cross-linking two or three purified Fab? “These chemical methods are not suitable for commercial use due to their high cost, lengthy production process, purification procedures, low yields of 20%, and heterogeneous product.

Discrete VH- and VL-domains of antibodies made by recombinantDNA technology may pair together to form a dimer with binding ability (U.S. No. 4,642,334). Nevertheless, these non-covalently linked molecules are not stable enough under physiological conditions for any practical application. The VH and the VL domains of a VH or VL homologous molecule can be linked with a peptide of suitable composition and length, usually consisting of at least 12 amino acids residues to produce a single-chain Fv with binding activity. In U.S. Pat., methods of producing scFvs with multivalency and multiple specificity were revealed by changing the length of the linker. Nos. Nos. Low expression levels, heterogeneous product, instability in solution resulting in aggregates, instability in serum and impaired affinity are all common problems.

Interferons play a critical role in antitumor defense and antimicrobial host defence. They have been extensively investigated as therapeutic agents against cancer and infectious diseases (Billiau, et. al. 2006, Cytokine growth factor Rev 17:381-409, Pestka, et. al. 2004, Immunol Review 202:8-32). Although there have been considerable efforts made with type I and interferons, (IFN -?/? IFN-?/? The use of these drugs in clinical settings has been restricted due to their short circulation half-life and systemic toxicity. In early 2003, the discovery of IFN-? family agents opened up a new avenue for developing alternative IFNs to treat these unmet indications. (Kotenko, Sheppard, et. al. 2003, Nat. Immunol. 4:69-77, Sheppard, et. al. 2003, Nat. Immunol. 4:63-8).

The therapeutic efficacy of IFNs is confirmed by the approvals of IFN-2 for treating hairy-cell leukemia and chronic myelogenous lymphoma; IFN-3 for treating multiple sclerosis and IFN-4 for treating AIDS-related Kaposi sarcoma and chronic hepatitis B or C. “The therapeutic effectiveness of IFNs has been validated to date by the approval of IFN-?2 for treating hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma and condylomata acuminata; AIDS-related Kaposi sarcoma; chronic hepatitis B and C. Chronic granulomatous diseases and malignant osteopetrosis are treated with IFN-? Although there is a large literature on autocrine and parachrine cytokines in health and illness, the functions of these cytokines are still being clarified, and new and more effective forms are being introduced to clinical practice (Pestka 2007, J. Biol. Chem 282 :20047-51 ; Vilcek, 2006, Immunity 25, 343-48. “The effects of combining various interferons and antibody-based therapy also remain to be investigated.

These A The A Numerous other candidate ADCs are currently in clinical testing, such as inotuzumab ozogamicin (Pfizer), glembatumomab vedotin (Celldex Therapeutics), SAR3419 (Sanofi-Aventis), SAR56658 (Sanofi-Aventis), AMG-172 (Amgen), AMG-595 (Amgen), BAY-94-9343 (Bayer), BIIB015 (Biogen Idec), BT062 (Biotest), SGN-75 (Seattle Genetics), SGN-CD19A (Seattle Genetics), vorsetuzumab mafodotin (Seattle Genetics), ABT-414 (AbbVie), ASG-5ME (Agensys), ASG-22ME (Agensys), ASG-16M8F (Agensys), IMGN-529 (ImmunoGen), IMGN-853 (ImmunoGen), MDX-1203 (Medarex), MLN-0264 (Millenium), RG-7450 (Roche/Genentech), RG-7458 (Roche/Genentech), RG-7593 (Roche/Genentech), RG-7596 (Roche/Genentech), RG-7598 (Roche/Genentech), RG-7599 (Roche/Genentech), RG-7600 (Roche/Genentech), RG-7636 (Roche/Genentech), anti-PSMA ADC (Progenics), lorvotuzumab mertansine (ImmunoGen), milatuzumab-doxorubicin (Immunomedics), IMMU-130 (Immunomedics), IMMU-132 (Immunomedics) and antibody conjugates of pro-2-pyrrolinodoxorubicin. (See, e.g., Li et al., 2013, Drug Disc Ther 7:178-84; Firer & Gellerman, J Hematol Oncol 5:70; Beck et al., 2010, Discov Med 10:329-39; Mullard, 2013, Nature Rev Drug Discovery 12:329, Provisional U.S. Patent Application 61/761,845.) A

Another promising immunotherapy approach involves the use of antagonistic antibody against immune checkpoint protein (e.g. Pardoll 2012, Nature Reviews Cancer, 12:252-64). Immune checkpoints are endogenous inhibitory pathways that regulate immune system function. They maintain self-tolerance, and modulate duration and extent immune response to antigenic stimuli (Pardoll 2012). It appears that certain pathogens and tumor tissues may co-opt this system in order to reduce the effectiveness and speed up the growth of the host immune response. This can lead to chronic infections and tumor growth (e.g. Pardoll 2012, Nature Reviews Cancer, 12:252-64, Nirschl and Drake 2013, Clin Cancer Research, 19:4917-24). Checkpoint molecules are CTLA4(cytotoxic T-lymphocyte antigen-4), PD1(programmed-cell-death-protein 1), PDL1 (programmed-cell-death-ligand 1) and many others. (Pardoll 2012, Nature Reviews Cancer, 12:252-64, Nirschl & Draes, 2013, Clin Cancer Research 19:4917-24). Clinical trials are underway for antibodies against CTLA4, PD1, PDL1, and other checkpoint molecules. These have shown surprising efficacy in treating tumors resistant to standard treatment.

There is a need for improved methods and compositions that can generate bispecific antibodies with improved properties such as longer T1/2, improved pharmacokinetics, improved in vivo stabilty, and/or increased in vivo effectiveness. Combination therapies are also needed to enhance the efficacy and effectiveness of treatments that aim to induce an immune response to various diseases such as cancer, infectious disease or cancer.

The present invention relates to combination therapy with two or more agents selected from the group consisting of a leukocyte-redirecting complexes, interferons, checkpoint inhibitor antibodies, and antibody-drug conjugates (ADCs). The first three types of agents may be used to induce or enhance the immune response against disease-associated antigens, such as tumor-associated antigens (TAAs) or pathogen (micro-organism)-expressed antigens. ADCs can be combined with immunomodulatory agents in order to reduce tumor burden, and improve overall treatment efficacy.

In embodiments utilizing leukocyte-redirecting complexes, the complexes preferably are bispecific antibodies (bsAbs), with one binding site against a leukocyte expressed antigen and a second binding site that binds to a target antigen on a tumor cell or pathogen (i.e., micro-organism). The The Mon The The The

An exemplary bsAb design disclosed in the Examples below combined a anti-CD3 F(ab), with an anti CD19 scFv, to form a (19)-3s construct that specifically targeted B-cells. Other bsAbs that combine anti-CD3 and antibody fragments against tumor-associated antigens are used in targeted leukocyte-immunotherapy for various solid tumors. These bsAbs will be discussed more in detail below. This design has the advantages of bivalent binding with tumor cells, larger size (>130 kDa), which prevents rapid renal clearance and powerful leukocyte-mediated cytotoxicity. The bsAbs “mediate the formation immunological synapses with leukocytes, induce leukocyte proliferation and activation in the presence target cells and inhibit growth of tumors in vivo.

The antibodies or fragments thereof can be chimeric human-mouse, humanized (human framework and murine hypervariable (CDR) regions), or fully human. The antibodies, or fragments of them, can be humanized (human framework with murine hypervariable regions (CDR), or fully-human, or variations thereof. ), as described by van der Neut Kolfschoten et al. (Science 2007; 317:1554-1557). The antibodies or fragments of the antibodies may be selected or designed to contain human constant region sequences belonging to specific allotypes. This may reduce immunogenicity in a human when administered. Allotypes that are preferred for administration include non-G1m1 (nG1m1) allotypes, such as G1m3, G1m3,1, G1m3,2, or G1m3,1,2. The allotype should be selected from the group of nG1m1, nG1m1,2, and Km3 allotypes.

Other preferred embodiments concern compositions and/or use of leukocyte-redirecting complexes in combination with one or more checkpoint inhibitor antibodies. These antibodies have an antagonistic effect on checkpoint inhibitor function. There are many such antibodies in the literature, including lambrolizumab, nivolumab, pidilizumab, AMP-224, MDX-1105, MEDI4736, MEDI4736A, MPDL3280A, BMS-936559, Bristol-Myers Squibb, ipilimumab, Bristol-Myers Squibb, and tremelimumab, Pfizer. Anti-KIR antibody such as lirlumab and IPH2101 from Innate Pharma may have similar functions on NK cells. “Any known checkpoint-inhibitor antibody can be used with one or more other agents.

Interferons are another agent that can be used together. The art is aware of the use of interferons, which may include interferon?, Interferon?, Interferon?1, 2, or 3. The interferon should be interferon?. The interferon can be administered in a number of forms, including free interferon or PEGylated, interferon-fusion proteins, interferon-conjugated to an antigen, and interferon conjugated with an antibody.

In A A Numerous other candidate ADCs are currently in clinical testing, such as inotuzumab ozogamicin (Pfizer), glembatumomab vedotin (Celldex Therapeutics), SAR3419 (Sanofi-Aventis), SAR56658 (Sanofi-Aventis), AMG-172 (Amgen), AMG-595 (Amgen), BAY-94-9343 (Bayer), BIIB015 (Biogen Idec), BT062 (Biotest), SGN-75 (Seattle Genetics), SGN-CD19A (Seattle Genetics), vorsetuzumab mafodotin (Seattle Genetics), ABT-414 (AbbVie), ASG-5ME (Agensys), ASG-22ME (Agensys), ASG-16M8F (Agensys), IMGN-529 (ImmunoGen), IMGN-853 (ImmunoGen), MDX-1203 (Medarex), MLN-0264 (Millenium), RG-7450 (Roche/Genentech), RG-7458 (Roche/Genentech), RG-7593 (Roche/Genentech), RG-7596 (Roche/Genentech), RG-7598 (Roche/Genentech), RG-7599 (Roche/Genentech), RG-7600 (Roche/Genentech), RG-7636 (Roche/Genentech), anti-PSMA ADC (Progenics), lorvotuzumab mertansine (ImmunoGen), milatuzumab-doxorubicin (Immunomedics), IMMU-130 (Immunomedics) and IMMU-132 (Immunomedics). (See, e.g., Li et al., 2013, Drug Disc Ther 7:178-84; Firer & Gellerman, J Hematol Oncol 5:70; Beck et al., 2010, Discov Med 10:329-39; Mullard, 2013, Nature Rev Drug Discovery 12:329.) When

In certain embodiments the combination therapy can be used to treat cancer. Any type of cancer antigen and tumor type is expected to be targeted. Cancers such as acute lymphoblastic, acute myelogenous, biliary, cervical, esophageal and head and neck, Hodgkin lymphoma and lung cancer may be targeted. The skilled artisan, however, will recognize that tumor-associated antibodies are available for almost any type of cancer.

The CD

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