Invented by Rekha Bansal, Novelmed Therapeutics Inc

The market for the use of human anti-factor C3 antibody in inhibiting complement activation is rapidly growing due to its potential in treating a wide range of diseases. Complement activation is a crucial part of the immune response, but when dysregulated, it can lead to various inflammatory and autoimmune disorders. Anti-factor C3 antibody therapy offers a promising approach to modulate complement activation and restore immune balance. Complement activation plays a vital role in defending the body against pathogens and clearing damaged cells. However, excessive or uncontrolled complement activation can cause tissue damage and contribute to the pathogenesis of several diseases, including autoimmune disorders like rheumatoid arthritis, lupus, and multiple sclerosis. Additionally, complement dysregulation has been implicated in various inflammatory conditions such as age-related macular degeneration, ischemia-reperfusion injury, and transplant rejection. Human anti-factor C3 antibodies are designed to specifically target and inhibit the activity of factor C3, a central component of the complement cascade. By blocking factor C3, these antibodies can prevent the downstream activation of the complement system, thereby reducing inflammation and tissue damage associated with complement-mediated diseases. The market for human anti-factor C3 antibody therapy is driven by the increasing prevalence of autoimmune and inflammatory disorders worldwide. According to the American Autoimmune Related Diseases Association, approximately 50 million Americans suffer from autoimmune diseases, and the numbers are rising. This growing patient population presents a significant market opportunity for innovative therapies like anti-factor C3 antibodies. Furthermore, the limitations of current treatment options for complement-mediated diseases have created a demand for more effective and targeted therapies. Traditional immunosuppressive drugs used in autoimmune disorders often have significant side effects and may not adequately control complement activation. Anti-factor C3 antibody therapy offers a more specific and potentially safer approach to modulating complement activation, making it an attractive option for both patients and healthcare providers. Several pharmaceutical companies and biotechnology firms are actively developing human anti-factor C3 antibodies. These companies are investing in research and clinical trials to demonstrate the safety and efficacy of their antibody candidates. The market competition is driving innovation and pushing for the development of more potent and selective antibodies. In addition to autoimmune and inflammatory diseases, the potential applications of human anti-factor C3 antibody therapy extend to other areas such as transplantation medicine and rare complement-mediated disorders. Transplant rejection, for instance, involves complement activation, and inhibiting this process with anti-factor C3 antibodies could improve graft survival rates. Furthermore, rare genetic disorders caused by complement dysregulation, like paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, could also benefit from targeted anti-factor C3 antibody therapy. In conclusion, the market for the use of human anti-factor C3 antibody in inhibiting complement activation is expanding rapidly. With the increasing prevalence of complement-mediated diseases and the limitations of current treatment options, there is a growing demand for more effective and targeted therapies. Human anti-factor C3 antibodies offer a promising approach to modulate complement activation and restore immune balance, making them an attractive option for patients and healthcare providers. Continued research and development in this field will likely lead to the introduction of novel and improved anti-factor C3 antibody therapies in the near future.

The Novelmed Therapeutics Inc invention works as follows

The method includes the administration of a C3B-inhibitor to the subject in order to inhibit C3b binding factors B and Properdin, C3 cleavage and activation of monocytes and platelets.

Background for Use of human anti-factor C3 antibody in inhibiting complement activation

The complement system is a series chemical reactions within the immune system that aid in the removal and elimination of pathogens. It also provides an early-acting mechanism for initiating and activating an inflammatory response against microbial infections and other acute insults. Complement activation is a first-line defense that can be very effective against pathogens. However, complement’s activities which promote an inflammatory response to protect the host may also pose a threat. Neutrophils, for example, are activated when C3 or C5 proteolytic product is released. They release destructive enzymes that may cause organ damage. Complement activation can also result in host cell lysis, resulting from the deposition on both microbial targets and host cells of lytic complement component.

There are implications that complement contributes to the pathogenesis in many acute and chronic diseases, such as septicshock, capillary leakage after thermal burns, myocardial ischemia, transplant rejection revascularization, stroke, ARDS and reperfusion injury. Other conditions include rheumatoid, multiple sclerosis and myasthenia. Complement is not the primary cause of nearly all these conditions. However, it could be an important pathological mechanism and offer a point of control for clinical treatment. Growing recognition of the role of complement-mediated injury in various disease states indicates the need for effective inhibitory drugs. “Despite this, there are currently no approved drugs for use by humans that target and inhibit complement activity.

The complement system is activated by three distinct pathways. These are the classical pathway (also known as the antigen pathway), the lectin path, and the alternate pathway. The classical pathway can be triggered most commonly by an antibody that is bound to an antigen (i.e. a foreign particle). This requires prior exposure to the antigen. While the classical complement pathway is part of the acquired immunity system and requires antibodies to activate, the alternative pathway can be triggered by C3 hydrolysis, or antigens, without prior exposure to antibodies.

The binding of C1q to IgG or IgM bound with antigen is the first step of activation of the classic pathway. C1q binding to an immune complex results in autoproteolytic C1r cleavage followed by C1r activation to C1s. C1s then gains the ability to cleave C4 or C2. C4 fragments into C4a, C4b and C4c. The C4b fragments can form covalent bonds to adjacent amino or hydroxyl groups. This allows C4b to generate C3 convertase by non-covalent interactions with the C2b of activated C2. C3 convertase, (C4b2b), activates C3, leading to the generation of C5 convertase, (C4b2b3b), and the formation of membrane attack complexes (C5b-9). “The activated forms (C3b, C4b) of C3b and C4 are covalently deposition on the surfaces of foreign targets that are recognized by multiple complement receptors in phagocytes.

For activation by the lectin path, the first step also is the binding of specific recognition molecules. This is followed by activation by associated serine proteases. The lectin path uses a similar protein to C1q in the classical complement pathway and allows binding of multiple pathogens. The recognition molecules of the lectin path are carbohydrate binding proteins (mannanbinding lectin, MBL and Ficolins), rather than immune complexes bound by C1q. MBL is a lectin with a calcium dependence that can activate the complement cascade through binding carbohydrates on pathogen surfaces.

During inflammation the expression of MBL increases and L-ficolin in serum is at similar levels as MBL. The L-ficolin lectin arm is therefore potentially equivalent in strength to that of the MBL lectin arm. Human MBL interacts with C1r/C1s serine proteases that are unique to the collagen-like domain of MBL. These MASPs (MBL-associated Serine Proteases) have a high affinity and form a specific interaction. C3b is a protease that activates C4 and C2 in order to produce the C3 converterase C4b2b. It is generally believed that the mannan binding lectin pathway plays a part in the host’s defense against infection. These patients are more susceptible to infection. Other studies have implicated both the classical and alternative paths in the pathogenesis ischemia/reperfusion injuries and the role for the lectin-pathway remains controversial.

The alternative pathway initiates the biochemical cascade through spontaneous activation by abnormal surfaces such as bacteria, damaged tissues, or virally-infected cells. The alternative pathway requires four plasma proteins that are directly involved. These include C3, factors D and B, and P. C3b must be cleaved from native C3 by proteolytic cleavage. C3 is a member of a protein family that includes C4 and?-2 macroglobulin. These proteins contain a rare modification called a thioester bond. The thioester groups are made up of glutamines whose terminal carbonyl groups are bound to the cysteine sulfhydryl groups three amino acids away. The bond formed is unstable, but it allows the electrophilic glutamine carbonyl group to form covalent bonds with other molecules through hydroxyl and amino groups. The thioester is relatively stable when it is isolated in a hydrophobic cavity of intact C3. The proteolytic cleavage from C3b to C3 results in the release a highly reactive and high-energy thioester on C3b. This mechanism allows C3b and an additional C3a molecule to be released.

The C3 thioester, in conjunction with its role in the covalent attachment to C3b targets by thioester, is thought to play a crucial role in the alternative pathway. The cascade provides an amplification loop that is powerful for both the C4b2b and the C3bBb. This is because any C3b produced can be combined with factor B to form additional alternative pathway C3 converterase. Inhibition of C3b will therefore inhibit all three pathways, complementing system activation. Binding of properdin stabilizes the alternative pathway C3 converterase, extending its half-life by six to ten times. The addition of C3b leads to the formation alternative pathway C5 converterase.

Each of the three pathways, (lectin, alternative and classic) are thought to converge on C3, which is then cleaved into products with multiple proinflammatory effects. The C5 converterase releases the strongest anaphylatoxin C5a by cleaving C5. It also induces changes in smooth muscle tone and vascular permeability, and is a powerful chemotaxin. C5a-mediated activation of cells can significantly increase the inflammatory response through the induction and release of additional mediators such as cytokines. hydrolytic enzymes. arachidonic acids metabolites, and reactive oxygen species. C5 cleavage can also lead to C5b, which is the precursor of C5b-9 or the membrane attack compound (MAC). There is evidence that sublytic MAC plays an important role in inflammation, as well as its role of a lytic pore forming complex.

According to the clinical and research evidence, it appears that the activation pathways of complement are responsible for the production of C3a, C5a, and C5a activation in the majority of acute and chronic conditions. In clinical settings both C3a as well as C5a are involved. Therefore, it would be desirable to develop suitable inhibitors for all pathways. It is known that both C3a C5a anaphylatoxins activate platelets and leukocytes. Cellular expression of CD11b by leukocytes and CD62P by platelets is a frequent indicator of cell activation. These activation markers mediate the binding of platelets to leukocytes, which triggers several inflammatory molecules. This conjugate formation can lead to platelets being removed from circulation. This phenomenon can contribute towards the development of thrombocytopenia.

The present invention is a method for inhibiting C3b-dependent complement activation. This involves limiting C3 cleavage and limiting the binding of C3b with factor B, or C3b with properdin. C3-dependent complement activation may be inhibited using a C3 inhibition molecule. C3 inhibitor molecules can be made up of whole or fragmented anti C3 antibodies. The fragmented C3 antibody can either be F(ab), Fv or single-chain Fv. The anti-C3 antibodies can be monoclonal or polyclonal. They may also be chimeric or de-immunized. The present invention discloses anti C3/C3b antibody for treatment of various disease conditions involving problematic complement activation.

One aspect” of the invention is a method for inhibiting the negative effects of C3b dependent complement activation on a subject. The method involves administering a C3b inhibiting agent to the subject in an amount that is effective at inhibiting C3b dependent complement activation. The phrase “C3b dependent complement activation” is used in this context. The activation of the three complement pathways is referred to as “C3b-dependent complement activation”. In certain aspects of the invention the C3b inhibity agent is an antibody or fragment thereof against C3b, and in other aspects the anti-C3b antibodies have reduced effector functions. C3b inhibiting agent can also be a C3b-inhibitory peptide.

The invention describes methods, compositions and medicaments that are effective in inhibiting adverse effects of C3b dependent complement activation, in vivo, in mammalian subject, including humans with an acute or chronic condition or injury, as described further herein. These conditions and injuries include without limitation C3b-mediated complement activation associated with autoimmune disorders or inflammatory conditions.

In one aspect, the invention provides methods for treating ischemia-reperfusion injuries in a subject who has undergone ischemic reperfusion. This includes, without limitation, cardiopulmonary by-pass, after aortic aneurism repair, vascular reconstruction in conjunction with, for instance, organ transplants, such as heart or lung transplants, kidney or liver transplants, extremity/digital replantation and hemodynamic resuscitation in the aftermath of shock, surgery, and/or other procedures.

In another aspect of the invention methods are provided to inhibit C3b dependent complement activation. This includes but is not limited too pancreatitis and ulcerative colitis. Diverticulitis, bowel disorders such as Crohn’s and irritable-bowel syndrome, also fall under this category. Inhibiting C3b dependent complement activation in a subject with a lung condition is another method. This includes, but is not restricted to, acute respiratory distress syndrome (ARDS), asthma, transfusion related respiratory depression (TRRD), transfusion-related lung injury (IRLI), ischemia/reperfusion lung injury, meconium-aspiration syndrome, chronic obstructive lung disease, Goodpasture’s syndrome, antiglomerular basement-membrane disease (“Goodpasture’s Disease”), Wegener’s Granulomatosis and emphysema.

The invention could also be applied to inhibiting C3B-dependent complement activation in a subject suffering from a musculoskeletal condition, including but not limited to osteoarthritis, rheumatoid arthritis, gout, juvenile rheumatoid arthritis, neuropathic arthropathy, psoriatic arthritis, ankylosing spondylitis or other spondyloarthropathies, and crystalline arthropathies, or systemic lupus erythematosus (SLE).

In another aspect of the invention methods are provided to inhibit C3b dependent complement activation, in a patient who has received, is undergoing, or will receive an extracorporeal procedure such as hemodialysis (ECMO), leukopheresis (Plasmapheresis), heparin induced extracorporeal LDL precipitation(HELP) (HELP), and cardiopulmonary bypass. The invention also provides methods for inhibiting C3b dependent complement activation after an organ transplant or other tissue donation, including but without limitation, allotransplantation and xenotransplantation (e.g. kidney, heart pancreas lung cornea etc.). or grafts (e.g., valves, tendons, bone marrow, etc.).

In still another aspect of the invention, methods are provided for inhibiting C3b-dependent complement activation in a subject suffering from renal conditions including but not limited to membranous glomerulonephritis, mesangioproliferative glomerulonephritis, acute postinfectious glomerulonephritis (poststreptococcal glomerulonephritis), cryoglobulinemic glomerulonephritis, lupus nephritis, membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), Henoch-Schonlein purpura nephritis or IgA nephropathy. A subject with a skin disorder, such as psoriasis or eosinophilic skin spongiosis is also included.

Another aspect of the invention includes methods for inhibiting C3b dependent complement activation. This may include but is not limited to male or female infertility and placental dysfunction, miscarriage, and pre-eclampsia. One aspect of the invention includes methods for inhibiting C3b dependent complement activation of a subject with nonobese diabetic (Type-1 diabetes, Insulin dependent Diabetes Mellitus), or complications such as angiopathy or neuropathy of Type-1 (adult-onset) or Type-2 diabetes.

In another aspect of the present invention, methods are provided for inhibiting C3b dependent complement activation, in a patient suffering from a central or peripheral nervous system injury or disorder. Multiple sclerosis, cerebral trauma, Huntington?s disease, myasthenia Gravis, Guillain-Barre syndrome, Amyotrophic Lateral Sclerosis (ALS), stroke reperfusion, degenerative disks, cerebral hemorrhage and/or trauma, Parkinson?s disease, Alzheimer?s disease, Miller-Fisher Syndrome, demyelination, and meningitis are all examples of conditions that can be treated by inhibiting C3b dependent complement activation. The inhibition of C3b dependent complement activation can also be used in subjects suffering from blood disorders, including sepsis and conditions resulting from it, such as severe sepsis. The methods are also applicable to other blood disorders such as hemorrhagic symptons, hemolytic anemias, autoimmune thrombotic-thrombocytopenic (TTP), hemolyticuremic syndromes (HUS), or other marrow/blood damaging conditions.

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