Invented by Dimiter S. Dimitrov, Zhongyu Zhu, US Department of Health and Human Services

The Market for Human Monoclonal Antibody that Binds Human Insulin-like Growth Factors and Its Use Human monoclonal antibodies (mAbs) have revolutionized the field of medicine by offering targeted therapies for various diseases. One such promising area of research is the development of mAbs that bind human insulin-like growth factors (IGFs). These antibodies have shown immense potential in the treatment of cancer, diabetes, and other growth-related disorders. Insulin-like growth factors (IGFs) are proteins that play a crucial role in cell growth, proliferation, and differentiation. They are structurally similar to insulin and bind to specific receptors on the cell surface, triggering a cascade of signaling pathways that regulate cell growth and survival. Dysregulation of IGF signaling has been implicated in various diseases, including cancer, diabetes, and certain genetic disorders. The development of mAbs that specifically bind to IGFs has opened up new avenues for targeted therapy. These antibodies can either block the interaction between IGFs and their receptors or directly target IGF-producing cells, leading to inhibition of IGF signaling and subsequent inhibition of cell growth. This targeted approach offers several advantages over traditional therapies, such as chemotherapy, which often have significant side effects due to their non-specific nature. The market for human monoclonal antibodies that bind human IGFs is rapidly expanding due to the growing demand for targeted therapies. The global cancer therapeutics market alone is projected to reach a value of $220 billion by 2025, with a significant portion of this market being driven by the demand for mAb-based therapies. Additionally, the prevalence of diabetes and other growth-related disorders is on the rise, further driving the need for innovative treatments. Several pharmaceutical companies and research institutions are actively involved in the development of mAbs targeting IGFs. These antibodies are typically developed using advanced techniques such as phage display or hybridoma technology. Once developed, they undergo rigorous preclinical and clinical testing to ensure their safety and efficacy. One of the most promising applications of these antibodies is in the field of oncology. Clinical trials have shown that mAbs targeting IGFs can effectively inhibit tumor growth and metastasis in various types of cancer, including breast, lung, and prostate cancer. These antibodies can be used as standalone therapies or in combination with other anti-cancer agents, such as chemotherapy or immune checkpoint inhibitors. In addition to cancer, mAbs targeting IGFs also hold promise in the treatment of diabetes. By inhibiting IGF signaling, these antibodies can improve insulin sensitivity and glucose metabolism, thereby helping to control blood sugar levels. Clinical trials are currently underway to evaluate the safety and efficacy of these antibodies in diabetic patients. Furthermore, mAbs targeting IGFs may have potential applications in other growth-related disorders, such as acromegaly and gigantism. These conditions are characterized by excessive growth due to overproduction of IGFs. By specifically targeting IGFs, these antibodies can potentially normalize growth and improve the quality of life for affected individuals. In conclusion, the market for human monoclonal antibodies that bind human IGFs is rapidly expanding, driven by the growing demand for targeted therapies in the fields of oncology, diabetes, and other growth-related disorders. These antibodies offer a promising approach to inhibit IGF signaling and regulate cell growth, with potential applications in various disease areas. Continued research and development in this field hold the key to unlocking the full therapeutic potential of these antibodies and improving patient outcomes.

The US Department of Health and Human Services invention works as follows

The compositions of antibodies and the methods of treatment for neoplastic diseases in mammalian subjects are described. The methods of diagnosing mammalian cancer are also described.

Background for Human monoclonal antibody that binds human insulin-like growth factors and its use

Cancer therapies are based upon the theory that cells with an accelerated rate of division and proliferation are predisposed to cancer. Recent epidemiologic studies show that high levels of insulin-like growth factors (IGFs)-I are linked to an increased risk of several cancers. These include those of the colorectum, breast, prostate and lung. IGFBP-3, a major IGFI-binding proteins in serum, which in most cases suppresses IGFI’s mitogenic activity, is inversely related to the risk of cancer.

IGF-I is a dual function protein that not only promotes cell proliferation, but also inhibits the apoptosis of cells. Combining these mitogenic effects with antiapoptotic ones can impact tumor growth. Members of the IGF Family, in addition to their direct impact on cancer-related cell activities, also interact with molecules involved in the development and progression of cancer, such as sex hormones, tumor suppressor gene products, and other growth factor. Nutrition and physical activity also affect the expression and production IGF-I. This peptide hormone is responsible for regulating growth and development in humans. The experiments to understand the cellular structure and physiologic functions of IGF members provide insight into the role that mitogenic growth factors play in carcinogenesis. Yu and Rohan J. Natl. Cancer Inst. 92: 1472-1489, 2000.

IGFs promote the proliferation of human breast cancer cell cultures. This stimulation is mediated by the insulin-like receptor 1 (IGFR-1), a member receptor tyrosine kinase. IGFR1 is activated by IGF-I and IGF-II, and phosphorylates tyrosine on IRS-1 and Shc. These two substrates then signal via the Ras/Raf, and phosphatidylinositol 3-kinase/AKT pathway. IGFR1 is crucial in the transformation process. “Cells derived IGFR1-knockout mice are resistant against transformation by various viral or cellular oncogenes including SV40 Large T Antigen and activated ras. However, fibroblasts from wild type mice can easily be transformed by these oncogenes.

There is growing epidemiological evidence that links elevated plasma IGF I level with prostate cancer, breast cancer, and colon carcinoma risk. Breast cancer tissue from patients has higher IGFR1 than adjacent normal tissues, suggesting a relationship between IGFR1-induced breast epithelial cells transformation. The transformation ability of tumor cells has been shown to be attenuated by inhibiting IGFR1 using antisense strategies, neutralizing antibodies (anti-IR3 and anti-IGF-1), or dominant negative truncation. Hailey, J. et al, Molecular Cancer Therapeutics 1: 1349-1353, 2002; Maloney E. K., et al, Cancer Res. 63: 5073-5083, 2003; Burtrum D., et al, Cancer Res., 63: 8912-8921, 2003; Lu et al., J. Biol. Chem. 279: 2856-2865, 2004; Miyamoto et al., Clin. Cancer Res. 11: 3494-3502, 2005; Goya et al., Cancer Research 64: 6252-6258, 2004. “There is a need for improved multi-targeted therapies to treat metastatic cancers and neoplastic diseases.

The present invention is a general description of antibody compositions, and treatment methods for neoplastic diseases in mammalian subjects. The present invention also relates to diagnostic methods for neoplastic diseases in mammalian subjects. These compositions include monoclonal isolated antibodies that bind insulin-like factor I. A second set of compositions consists of monoclonal anti-insulin-like-growth-factor I antibodies, which are also cross-reactive and bind insulin-like-growth-factor II. Monoclonal antibodies can be isolated from human, nonhuman primate or rabbit antibodies, as well as rat, mouse and rat antibodies. For example, the isolated monoclonal antibodies that bind insulin-like factor I include m705 or m706. m708 & m708.2 are isolated human monoclonal antibodies that bind both insulin-like IGF and insulin-like IIGF. The monoclonal antibodies M705, m706, and m708.2 don’t bind to insulin. “m705 contains a sequence of VH and VL amino acids.

The isolated monoclonal antibodies bind to human insulin like growth factor I or human insulin like growth factor II and contain an amino-acid sequence in the heavy chain variable region, as described in SEQID NO: 7, or an amino-acid sequence that is at least 90 percent homologous to SEQID NO: 7.

The isolated monoclonal antibodies bind to human insulin like growth factor I or human insulin like growth factor II and contain an amino-acid sequence in the light chain variable region, as described in SEQID NO: 8, or an amino-acid sequence that is at least 90 percent homologous to SEQID NO: 8.

The invention provides an isolated monoclonal antigen that binds human insulin-like-growth factor I and II, containing amino acid sequences within their heavy-chain variable regions and light-chain variable regions, as shown in SEQ ID Nos. 7 and 8 respectively, or at least 90% homologous amino acid sequences, respectively. “A pharmaceutical composition containing one or more antibodies of the invention and a pharmaceutically accepted carrier is provided.

In a second aspect, the antigen provides at least one sequence of CDR, including but not limited to VL : Q S I (SEQ NO. 9),VL : A A S,VL : Q Q,VL : A A,VH : G G F S S S Y,VH : G G F T F,VH : G I I P L G I,VH : G I I P I,VH :G I,VH : The antibody can be an IgG1, IgG2, IgG3, IgG4, IgM or IgA1. Is it possible that the antibody is an IgG1? The antibody can be an IgG1 or IgG1 isotype. isotype. Is the antibody an IgG4 or not? The antibody is an IgG4 or IgG4? isotype. IgG1, IgG2, IgG3, IgG4, IgM or IgA1 can all be antibodies. The antibody could be IgG1? The antibody can be an IgG1 or IgG1 isotype. isotype. Isotype. The antibody can be an IgG4 or IgG4 isotype. isotype. The antibody can be classified as human, nonhuman primate (rabbit, rodent or mouse), rabbit, rodent or nonhuman primates.

The isolated monoclonal antibodies of the present invention have one or more of these characteristics: (i), inhibits IGF-1 binding or IGF-2 binding to IGF-1, (ii), inhibits IGF-1 binding or IGF-2 binding to IGF-1, or (iii), inhibits cell migration during a cell migration test.

In another aspect, an isolated monoclonal antigen of the present invention is found to have a dissociation constant (KD), which can be determined using surface plasmon resonance (SPR), with recombinant human Insulin-like Growth Factor I or human Insulin-like Growth Factor II as the analyte, and the antibody used as the ligand.

A monoclonal isolated antibody in a second aspect is capable of binding insulin-like factor I or insulin-like factor II human with a high binding affinity, such as 108 M?1 and higher. In a second aspect, an isolated monoclonal is shown to be capable of binding insulin-like factor I or insulin-like factor II. The binding affinity is about 109 M1 or higher. In a more detailed aspect, the monoclonal antibodies are intact antibodies, intact IgG1 antibodies, intact IgG2 anti-bodies, intact IgG3 anti-bodies, intact IgG4antibodies, intact IgM anti-bodies, intact IgA1 or IgA2 Antibodies, intact secretory IgA, intact IgD, or intact IgE, and the antibody has been glycosylated within a eukaryotic The isolated monoclonal antibodies can also be an antibody fragment, or a single-chain antibody. The monoclonal antibodies can be used. The antibody may be a F(ab? The antibody can be a F(ab? The antibody may be antigen specific.

The monoclonal antibodies of the invention are a binding-domain immunoglobulin protein that comprises (i) the variable heavy chains amino acids as shown in SEQ NO: 7, or a similar variable heavy chain sequence, fused with (ii), an immunoglobulin CH2 constant regions fused onto the hinge region and (iii), an immunoglobulin CH3 constant regions fused onto the CH2 constant area. The antibody can bind a predetermined protein with an equilibrium association constant, for example of at 108 M1, at 109 M1, or at 1010 M1.

In one aspect, the antibody contains at least one CDR sequence of: VL: Q S I S (SEQ ID NO: 9), VL A A S (SEQ ID NO 10),VL Q Q S Y P T F P G H (SEQID No 11),VH G G T F Y Y a??? – – – – – – – – – – – – – In one aspect, an antibody contains at least one of the following CDR sequences: VL Q S I (SEQ NO. 9), VL A A S(SEQ NO. 10),VL Q Q SY S TP S T F(SEQ NO. 11),VH G G T S S S YA (SEQ NO. 12),VH G I I P L G I A

A monoclonal human antibody isolated from human is provided that binds human insulin-like factor I and contains an amino acids sequence in the human heavy chain variable regions as described in SEQ NO: 1, or an amino acids sequence at least 90% similar to SEQ NO: 1. A human monoclonal is isolated which binds human insulin-like factor I. It contains an amino sequence in the human light chain variable area as described in SEQ NO: 2, or an amino sequence that is at least 90 percent homologous to SEQ NO: 2. A human monoclonal antigen that binds human insulin-like factor I and contains an amino acids sequence in the human heavy chain variable regions as described in SEQ NO: 3, or an amino acids sequence at least 90% similar to SEQ NO: 3. A human monoclonal is isolated which binds human insulin-like factor I. It contains an amino acids sequence in the human light chain variable area as described in SEQ NO: 4, or an amino acids sequence that is at least 90 percent homologous to SEQ NO: 4. A human monoclonal is isolated which binds human insulin growth factor I, human insulin growth factor II and an amino sequence in the human heavy chain variable regions as described in SEQ NO: 5, or an amino sequence that is at least 90 percent homologous to SEQ NO: 5. A human monoclonal isolated antibody that binds human insulin-like-growth factor I and human growth factor II is provided. The amino acid sequence is in the human light-chain variable region, as described in SEQ NO: 6, or a sequence at least 90% similar to SEQ NO: 6. “A pharmaceutical composition containing one or more antibodies of the invention, and a pharmaceutically accepted carrier

An isolated RNA is provided that encodes the heavy chain immunoglobulin or light chain immunoglobulin variables domain sequences of the protein/antibody in the present invention. The nucleic acids and a pharmaceutically accepted carrier are combined to form a pharmaceutical composition. The recombinant cells contain one or more nucleic acid sequences that encode the immunoglobulin domain sequences in the antibody of this invention. The host cell contains a nucleic sequence encoding a HC polypeptide containing a variable domain from an antibody. A second nucleic sequence encoding a LC polypeptide containing a variable domain from the antibody. “A method for preparing an antigen capable of binding both insulin growth factors I and II. The method comprises expressing the nucleic acids of the present invention into a host cell in conditions that allow expression of the nucleic acids, followed by the recovery of the antibodies.

The following method is described: “A method for detecting insulin-growth factor I in a specimen, which includes the following steps: (a), providing a test sample; (b), contacting the test sample with a monoclonal human antibody m708 (or m708.2) which binds to a polypeptide that contains insulin-growth factor I or insulin-growth factor II, under conditions that allow binding of polypeptide ligands to insulin-growth factor I or insulingrowth factor II;

The following method is described: “A method for detecting insulin-growth factor I in a specimen, which includes the following steps: (a), providing a test sample; (b), contacting the test sample with a monoclonal human antibody m708 (or m708.2) which binds to a polypeptide that contains insulin-growth factor I or insulin-growth factor II, under conditions that allow binding of polypeptide ligands to insulin-growth factor I or insulingrowth factor II;

The following method is described: “A method for detecting human growth hormone I in a specimen consists of providing a test sample; (b), contacting it with a monoclonal human antibody m705/m706 that binds to a polypeptide which contains human growth hormone I, under conditions which allow binding of polypeptide ligands to human growth hormone I; (c) detecting the binding of antibody m705/m706 in the tested sample. This detection indicates

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