Invented by JiJie Gu, Chung-Ming Hsieh, Zhen Wu, Enrico L. DiGiammarino, Feng Luo, Gerard B. FOX, John E. Harlan, Martin Schmidt, Ralf LOEBBERT, Reinhold Mueller, Ulrich Ebert, Volker Nimmrich, AbbVie Deutschland GmbH and Co KG, AbbVie Inc

The market for antibodies to receptors of advanced glycation products (RAGE) – and their uses Advanced glycation end products (AGEs) are a group of compounds that are formed when proteins or lipids react with sugars in a process called glycation. These AGEs can accumulate in various tissues and organs, leading to the development and progression of several chronic diseases, including diabetes, cardiovascular diseases, and neurodegenerative disorders. One of the key players in the interaction with AGEs is the receptor for advanced glycation end products (RAGE). RAGE is a transmembrane receptor that is expressed on various cell types, including endothelial cells, immune cells, and neurons. It plays a crucial role in mediating the detrimental effects of AGEs by activating inflammatory and oxidative stress pathways. In recent years, there has been a growing interest in developing antibodies that specifically target RAGE. These antibodies can bind to RAGE and block its interaction with AGEs, thereby preventing the downstream signaling cascades that lead to tissue damage and disease progression. The market for antibodies to RAGE has witnessed significant growth due to the increasing understanding of the role of RAGE in various pathological conditions. The potential uses of antibodies to RAGE are vast and diverse. One of the primary applications is in the treatment of diabetic complications. Diabetes is characterized by elevated levels of AGEs, which contribute to the development of diabetic nephropathy, retinopathy, and neuropathy. By blocking RAGE, antibodies can potentially mitigate the harmful effects of AGEs and provide therapeutic benefits to diabetic patients. Furthermore, antibodies to RAGE have shown promise in the treatment of neurodegenerative disorders such as Alzheimer’s disease. AGEs and RAGE have been implicated in the pathogenesis of Alzheimer’s, contributing to neuroinflammation and neuronal dysfunction. Antibodies that target RAGE can potentially reduce the accumulation of toxic proteins and alleviate cognitive decline in Alzheimer’s patients. In addition to therapeutic applications, antibodies to RAGE also have diagnostic potential. The detection of RAGE expression levels in tissues or body fluids can serve as a biomarker for disease progression and prognosis. Antibodies can be used in various diagnostic techniques, including immunohistochemistry and enzyme-linked immunosorbent assays (ELISA), to quantify RAGE levels and monitor disease status. The market for antibodies to RAGE is expected to witness substantial growth in the coming years. The increasing prevalence of chronic diseases, coupled with the growing understanding of the role of RAGE in disease pathogenesis, is driving the demand for targeted therapies. Pharmaceutical companies and research institutions are investing in the development of novel antibodies and therapeutic strategies to target RAGE, further fueling market growth. However, there are challenges that need to be addressed in this market. One of the primary concerns is the development of antibodies with high specificity and affinity for RAGE. The design and optimization of antibodies require extensive research and development efforts to ensure their safety and efficacy. Additionally, the high cost of antibody production and the regulatory hurdles associated with drug development pose barriers to market growth. In conclusion, the market for antibodies to receptors of advanced glycation products (RAGE) is expanding rapidly due to the increasing understanding of the role of RAGE in various chronic diseases. These antibodies hold significant therapeutic and diagnostic potential in the treatment and management of conditions such as diabetes, cardiovascular diseases, and neurodegenerative disorders. However, further research and development efforts are needed to overcome challenges and fully unlock the potential of antibodies to RAGE in improving patient outcomes.

The AbbVie Deutschland GmbH and Co KG, AbbVie Inc invention works as follows

The present application is a monoclonal antibody, namely CDR-grafted humanized antibodies that bind RAGE protein. These antibodies can inhibit RAGE’s binding to various ligands. The antibodies, or portions thereof, described in this application can be used to treat a disorder or disease characterized or induced pathophysiological RAGE ligands. For example, misfolded proteins such as amyloid? and advanced glycation-end-products.

Background for Antibodies to receptors of advanced glycation products (RAGE) – and their uses

Alzheimer’s Disease (AD), the most common cause of dementia in the elderly, affects about 10% of those over 65 years old. As you age, your risk of developing disease increases. Around 15 million people are affected by the disease worldwide. With further life expectancy increases, the number of affected people is expected to triple in the coming decades. A treatment for AD is urgently needed in light of all the above. A treatment for AD may allow patients to live a more active and functional lifestyle, extending their lives beyond what is possible without it. Not only is there a financial impact, but also a ‘quality of life’?implication for such a therapy? “There are also implications for patients and their caregivers.

From a cellular point of view AD is characterized as a deposit abnormally aggregated protein. These deposits are mostly amyloid-?peptide filaments in extra-cellular plaques. In the case of intracellular neurofibrillary plaques (NFTs), the majority of these deposits are made up of tau protein. AD is also characterized as an increase in RAGE expression on neurons. RAGE is an immunoglobulin receptor that functions as a cell surface acceptor of A?.

A?40 injection in mice was shown by several studies to cause vasoconstriction in cerebral vessels, and a reduction in cerebral blood flow. The cerebral blood flow is also decreased in AD patients. RAGE is implicated in the progression of AD in mouse models where transgenic animals overexpress Amyloid Precursor protein (APP), which leads to plaque formation. Nature Medicine 9(7) pp 907-913, 2003; Arancio et al. EMBOJ, 1-10, 2004).

RAGE has shown to bind A?-peptides. The inhibition of this interaction inhibits the accumulation of A? RAGE may be involved in AD in the transgenic model. The treatment with anti-RAGE and sRAGE (soluble rage) antibodies as well as sRAGE has shown to reduce plaque numbers (Deane, 2003). Antibodies that block the interaction between RAGE and amyloid could be used to treat AD patients. However, the existing polyclonal antibody generated from animal serum is not suitable for chronic treatment in humans.

In WO 2006/077101 A1, it is described that RAGE lacking the v-domain competes with A? “Interaction of RAGE with A? The competition between peptides that represent parts of the C1-domain of RAGE and RAGE lacking the v-domain is described in WO 2006/077101 A1. In WO2007109749 (A2), the interaction of anti-RAGE antibody with the v domain of RAGE was described. In WO2007109749(A2), the interaction of anti-RAGE antibodies with the v-domain of RAGE is disclosed. This document also describes that binding of different ligands (S100b, HMGB1 (High Mobility Group Box 1 protein), amyloid a?)

WO 2008/137552A2 discloses monoclonal antibodies that bind to different RAGE domains.” The majority of these antibodies inhibit human RAGE’s interaction with a complex of HMGB1 DNA and CpG DNA.

The peptides AGER-RME, AGER CDP and RAGE-RME are described in WO2006/077101. These peptides can be used, among other things, to identify and prepare RAGE-binding ligands such as anti-RAGE antibody.

The present invention describes monoclonal antibody that binds to the C-domains in RAGE, and the specific interactions and competition with A? The present invention describes novel monoclonal antibody that binds to the C-domains of RAGE and the specific interaction and competition with A?

The present invention provides binding molecule, in particular antibodies that bind specifically RAGE. Representative anti-RAGE antibody of the invention can comprise at least one amino acid sequence from the antibody variable regions shown in SEQID NOs: 1, 2, 5, 9, 13, 17 and 21, or CDRs of these sequences or related CDRs as described in greater detail below.

The present invention provides monoclonal antibody that binds to RAGE. More specifically, it provides monoclonal antibody that binds to the C domain of RAGE.

The present invention includes anti-RAGE antibody that binds specifically to RAGE, and that has a variable light chain region with an amino acid sequence at least 90% identical to SEQ ID Nos. The sequences are: 5, 13, 21, or a RAGE binding fragment of an antigen-binding antibody.

Also, included are anti RAGE antibodies which bind specifically RAGE and have a heavy-chain variable region with an amino acid sequence at least 90% identical to SEQ ID Nos. The sequences are: 1, 9, 17, or a RAGE binding fragment of an antigen-binding antibody.

The present invention describes monoclonal antibody 11E6, which binds to the C-2 domain of RAGE and blocks the binding of A-globulomers. The present invention is more specific, describing monoclonal anti-body 11E6, that binds to C-2 domains of RAGE and does not bind to amino acid sequences which are used to create polyclonal antibodies. It can also neutralize the effects of A?1-40 in the cerebral vasculature of mice in vivo.

The anti-RAGE antibody of the invention includes antibodies that bind to the C domain of RAGE.

The anti-RAGE antibodies described in the invention are an anti-RAGE or RAGE-binding fraction as described above. This fragment is chosen from the following groups: a chimeric antigen, a CDR grafted or humanized antigen, a single-chain antibody, or a fusion-protein, or a human antigen.

In various embodiments of the invention, the antibodies are monoclonal or recombinant. The neutralizing antibodies in the present application, such as mAb7F9 and mAb11E6, as well as functional antibody fragments of these antibodies, are described here. Other antibodies and functional antibodies fragments that have similar properties, including high affinity binding to the RAGE polypeptide with low dissociation rates and high neutralizing capacities, are also intended to be part of the invention. Human antibodies in the present application may contain amino acids not encoded by the human germline immuneglobulin immunogenic polypeptide (or fragment thereof), which can be determined using any known method. The binding affinity, for example, can be determined by competitive ELISAs or c RIAs. BIAcore technology, KinExA, and BIAcore are also options. BIAcore and KinExA can also be used to measure the dissociation rate. Surface plasmon resonance, e.g. BIAcore, is used to measure the binding affinity and dissociation rates.

One of monoclonal antibody of the present application is the mAb7F9, which has at least 90 percent amino acid sequence similarity with a sequence containing a heavy-chain variable region (VH Region) containing the sequence of SEQID NO: 1, and SEQID NOs. The residues 31, 35, 50-68 and 101-108 from SEQ ID No: 1 are 2, 3, and 4. The mAb7F9 of the present invention shares at least 90% of its amino acid sequence with a sequence containing a light-chain variable region (VL) containing the sequence of SEQID NO: 5 and SEQID NOs. “6, 7, and 8, which are residues 24 to 34, 50-56, 90-97, of SEQ NO: 5 respectively.

Another monoclonal antibody of the present application is the mAb11E6. It has at least 90 percent amino acid sequence similarity with a sequence containing a heavy-chain variable region (VH Region) containing the sequence of SEQID NO: 9, and SEQID NOs. The residues 31, 35, 50-66 and 99-109 from SEQ ID No: 9 are 10, 11, and 12. The mAb11E6 antigen of the present invention shares at least 90% of its amino acid sequence with a sequence containing a light-chain variable region (VL) containing the sequences of SEQID NO: 13 and SEQID NOs. The residues 24, 34, 50-56 and 89-97 from SEQ ID No: 13 are respectively 14, 15, 16 and 17. The mAb11E6 is capable of binding to the C-2 RAGE domain, but does not bind to amino acid sequences that are used to produce polyclonal antibody. It can also neutralize the effects of A?1-40 in mice’s cerebral vasculature.

Another monoclonal antibody of the present application is the mAb4E5 antigen, which has at least 90 percent amino acid sequence similarity with a sequence containing a heavy-chain variable region (VH Region) containing the sequence of SEQID NO: 17 and SEQID NOs. The residues 31, 35, 50-66 and 99-109 from SEQ ID No: 17 are represented by 18, 19, and 20, respectively. The mAb4E5 antigen of the present invention shares at least 90% of its amino acid sequence with a sequence containing a light-chain variable region (VL) containing the sequence of SEQID NO: 21 and SEQID NOs. 22 23, and 24, which are residues 24 to 34, 50-56 and 89-97 from SEQ ID No: 21 respectively.

It is intended that the monoclonal antibody that interacts with RAGE in the present application can be a glycosylated protein, wherein the antigen-binding or antibody portion of it contains one or more carbohydrates residues. Post-translational modifications can be applied to the in vivo production of proteins. Enzymatically, glycosyl residues (sugars) can be added, a procedure known as “glycosylation”. Glycosylated proteins and glycoproteins are proteins that have oligosaccharide chains covalently attached. The amino acid sequence and host cell of the protein are important factors in determining the glycosylation of that protein. Different organisms can produce different glycosylation proteins (e.g., glycosyltransferases) and have different substrates available (nucleotide glucoses). Due to these factors, the glycosylation pattern of a protein, as well as the composition of glycosyls residues may vary depending on the host in which it is expressed. “Glycosyl residues that are useful for the invention include but are not restricted to glucose, galactose mannose fucose n-acetylglucosamine, and sialic acids.

The antibodies in the present application contain a constant heavy chain region such as IgG1, IgG2, IgG3, IgG4, IgA IgE IgM IgD constant regions. The antibody may also contain a constant light-chain region. This can be either a lambda or kappa constant light-chain region. The antibody contains a kappa constant light chain region. The antibody fragment can also be a Fab or Fv fragment with a single-chain. The art is aware of the possibility of replacing amino acid residues within the Fc portion in order to change the antibody effector’s function (Winter et. al.). U.S. Pat. Nos. 5,648,260; 5,624,821). The Fc part of an antigen mediates several key effector functions. e.g. e.g. These effector functions can be desirable in some cases, but they may also be undesirable or even harmful depending on the therapeutic goals. Certain human IgGs, notably IgG1 or IgG3, can mediate ADCC via Fc? The complement C1q and Rs are respectively. The circulating half-life is determined by the Neonatal Fc Receptors (FcRn). In a third embodiment, at least one residue of an amino acid is substituted in the constant region, for instance the Fc region, of the antigen, so that the effector functions are altered.

Click here to view the patent on Google Patents.