RU2828013C1 - Compositions of anti-cd6 antibodies and methods of treating and reducing negative consequences of coronavirus, including covid-19 - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: disclosed are the use of a non- depleting anti-CD6 antibody that specifically binds to domain 1 of CD6, for the treatment of an infectious disease that leads to a cytokine storm or cytokine release syndrome, for the treatment of an infectious disease caused by a coronavirus, which leads to a cytokine storm or a cytokine release syndrome, and for the treatment of COVID-19. Also disclosed is a kit for treating a subject against COVID-19.

EFFECT: inventions extend the range of products for treating and reducing the negative consequences caused by infectious agents, especially coronaviruses, wherein said negative consequences include triggering a cytokine storm or cytokine release syndrome.

17 cl, 9 dwg, 5 tbl, 10 ex

Description

CROSS-REFERENCES TO RELATED APPLICATIONS

[001] This application claims priority from Indian Provisional Application No. 202041014994, filed April 4, 2020; and Cuban Provisional Application No. 2020-0027, filed April 17, 2020, which are incorporated herein by reference in their entirety.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[002] The present invention is directed to CD6 antibodies, including non-depleting CD6 antibodies, methods of use and compositions for treating and reducing adverse effects caused by infectious agents such as bacteria and viruses, especially coronaviruses, wherein said adverse effects include the initiation of a cytokine storm or cytokine release syndrome.

LEVEL OF TECHNOLOGY

[003] More than 100 years after the last pandemic (1918), the world is now in the midst of another pandemic caused by an RNA virus that the International Committee on Taxonomy of Viruses (ICTV) has named "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), and the disease it causes is called COVID-19. The virus belongs to the coronavirus family and has now spread to all continents and is therefore expected to remain for a long time.

[004] To date, 115 million people worldwide have been infected with the virus. While many have recovered, about 15% of confirmed cases progress to severe disease, with patients over 65 years of age being more likely to progress to severe disease. The fatality rate is about 3%, according to global data.

[005] The virus is mainly transmitted by airborne droplets from an infected patient through the nose, mouth, or eyes of another person. It takes 2 to 14 days for symptoms to develop in an infected patient, with an average of 5 days. Three types of coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2, are transmitted by airborne droplets and can replicate in the lower respiratory tract and cause pneumonia.

[006] According to the World Health Organization (WHO), nearly 80% of cases have mild-moderate infection (classified by cough and fever, but do not require hospitalization), 13.8% have severe infection, and 6.1% have critical infection. The average incubation period of infection is about 4-5 days before symptoms appear, with 97.5% of symptomatic patients developing symptoms within 11.5 days. When hospitalized, COVID-19 patients experience fever, dry cough, and sometimes shortness of breath. The SARS-CoV-2 viral load peaks within 5-6 days of symptom onset, and in severe cases, the infection progresses to acute respiratory distress syndrome (ARDS), approximately 8-9 days after symptom onset.

[007] Recent evidence suggests that pathogenic human coronaviruses (severe acute respiratory syndrome coronavirus [SARS-CoV] and SARSCoV-2 (COVID-19) bind to their target cells via angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells of the lung (type II, alveolar cells), intestine, kidney, and blood vessels. ACE2 expression is significantly increased in patients with type 1 or type 2 diabetes and hypertension treated with ACE inhibitors and angiotensin II type 1 receptor blockers (ARBs). This likely explains why patients over 65 years of age, who are usually associated with these comorbidities, are more susceptible to the disease. These patients exhibit symptoms similar to those of the SARS (severe acute respiratory syndrome) outbreak in 2002-2003, In particular, mild, cold-like symptoms including fever, cough, fatigue, shortness of breath, muscle aches, and loss of taste and/or smell. SARS-CoV-2 infection triggers a proinflammatory response in some patients that involves high levels of cytokines, including IL-6, fibroblast growth factor (FGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor, and vascular endothelial growth factor. IL-6 levels have been found to directly correlate with increased mortality and inversely correlate with lymphocyte count, suggesting that cytokine release syndrome may interfere with the adaptive immune response (Li, et al. "Coronavirus infections and immune responses" J 322 Med Virol. 2020 Apr; 92(4):42 4 -32).

[008] Once the lung is infected, the virus uses RNA polymerase to replicate in the alveolar cells and uses the cellular machinery to translate the RNA into proteins. Eventually, many viral particles are produced and released. This causes reinfection and the viruses can be transmitted to other people.

[009] There are no standard treatment options for COVID19 infections caused by this new virus. However, multiple drugs are being tested in combination, depending on the route of viral infection. Other drugs in development or in trials come from several companies specializing in vaccines and monoclonal antibody therapies. Roche’s Actemra (anti-1L6) is in clinical trials for COVID, having been repurposed for this indication from autoimmune diseases. Sanofi’s Kevzara is also an antibody that blocks IL6 and is in clinical trials. Regeneron is developing antibodies to the virus’s spike proteins, hoping to prevent them from interacting with the ACE2 receptor. Takeda is developing hyperimmune immunoglobulins from responders for passive immunity. CytoSorb therapy is based on an extracorporeal blood purification procedure that can effectively reduce excess levels of inflammatory mediators in critically ill patients.

[0010] The need for new and more effective therapeutics to treat the negative impact of COVID19 continues to grow, especially those targeting emerging infectious diseases and pathogens. Thus, there is a need to provide new and effective treatments to reduce the negative impact of COVID-19 and its variants.

SUMMARY OF THE INVENTION

[0011] According to the present invention, there is provided the use of an anti-CD6 antibody, including a non-depleting anti-CD6 antibody that specifically binds to domain 1 of CD6, for the treatment and amelioration of the effects of coronavirus, and in particular the novel coronavirus (COVID-19) and its variants. In particular, the anti-CD6 antibody of the present invention exhibits therapeutic activity by reducing the hyperactive immune response, such as high levels of cytokine expression.

[0012] According to the present invention, there is provided the use of an anti-CD6 antibody, including a non-depleting anti-CD6 antibody that specifically binds to domain 1 of CD6, for the treatment and reduction of the consequences of a bacterial infectious agent, and in particular group A streptococci and pneumococci. In particular, the anti-CD6 antibody of the present invention exhibits therapeutic activity by reducing a hyperactive immune response, such as high levels of cytokine expression.

[0013] Accumulating evidence suggests that some patients with severe COVID-19 experience a cytokine storm syndrome. Cytokines are inflammatory proteins of the immune system that are designed to fight infections and prevent cancer, but too many of them can cause the immune system to go crazy. The body's own immune killer cells, in such increased numbers, can lead to organ failure and death. Currently, respiratory failure due to acute respiratory distress syndrome (ARDS) is the leading cause of death in patients with COVID-19. Thus, the present invention provides a novel approach to reduce the amount of inflammatory cytokine proteins, which may include interleukins IL-1, IL-6, and IL-2 and interferon gamma, and to treat patients with hyperinflammation complications caused by COVID-19 and its variants.

[0014] In one aspect, the present invention also provides a method of treating a cell or organism infected with a coronavirus, comprising treating with a therapeutically effective amount of an anti-CD6 antibody comprising heavy and light chain variable regions comprising the amino acid sequences set forth in SEQ ID NO: 1 (heavy chain variable region) and 2 (light chain variable region) or an amino acid sequence having at least 98% identity thereto, comprising SEQ ID NO: 1 (heavy chain variable region) and 3 (light chain variable region) according to the present invention.

[0015] In another aspect, the present invention also provides a method of treating a cell or organism infected with a coronavirus, comprising treating with a therapeutically effective amount of an anti-CD6 antibody having heavy and light chain regions comprising or consisting of the amino acid sequences set forth in SEQ ID NO: 4 (heavy chain) and 5 (light chain) or amino acid sequences having at least 98% identity thereto according to the present invention. An anti-CD6 antibody comprising or consisting of SEQ ID NO: 4 and 6 is included in the present invention.

[0016] The antibody is administered to patients intravenously, in a dose range of from about 0.5 mg/kg body weight to about 8 mg/kg body weight. Doses of 1 mg/kg to 6 mg/kg are preferred. The antibody is preferably administered to the patient at least twice for a maximum of 5 doses. The time elapsed between two consecutive administrations will be from 24 to 96 hours. A preferred administration schedule consists of two to three doses at 72 hour intervals.

[0017] In another aspect, the present invention provides a method for alleviating the cytopathic destructive consequences of COVID-19 infection and its variants in a human patient, comprising administering to said patient a therapeutic amount of an anti-CD6 antibody comprising SEQ ID NO: 1 (heavy chain variable region) and SEQ ID NO: 2 (light chain variable region) or 3 (light chain variable region) according to the present invention.

[0018] In another aspect, the present invention provides therapeutic compositions comprising a therapeutic amount of an anti-CD6 antibody comprising the amino acid sequences of SEQ ID NO: 4 (heavy chain) and 5 or 6 (light chain) of the present invention in a pharmaceutically acceptable carrier. [0019] Furthermore, since the use of more than one active agent can provide an improved therapeutic composition, and this is especially true when the different agents act by different mechanisms, the present invention also includes therapeutic compositions comprising an anti-CD6 antibody comprising the amino acid sequences of SEQ ID NO: 4 (heavy chain) and SEQ ID NO: 5 or 6 (light chain) of the present invention together with one or more other antiviral agents, such as reverse transcriptase (RT) inhibitors that interfere with a critical step in the viral life cycle and prevent the virus from making copies of itself; Nucleoside analogues - a nucleoside analogue to inhibit coronavirus replication through lethal mutagenesis; Protease inhibitors - interfere with a protein that viruses use to make infectious viral particles; Fusion inhibitors - block the virus from entering the body's cells; Integrase inhibitors - can block an enzyme needed to make copies of itself; Multidrug combinations - combine two or more different types of drugs into one, and/or pharmacokinetic enhancers and biological response modifiers, including, for example, interferon (α, β, or γ), interleukin-2, and granulocyte-monocyte colony-stimulating factor ("GM-CSF"), etc.

[0020] The combination compositions of the present invention may contain reduced doses of the active antiviral agent while maintaining the level of antiviral activity characteristic of a higher dose. As a result, the cytotoxicity normally associated with the administration of the antiviral agent is minimized by the administration of the combination compositions of the present invention. Thus, the combination compositions may contain a reduced dose of the antiviral agent in combination with the CD6 antibody of the present invention to achieve a level of antiviral activity that is higher than normally required while maintaining an acceptable level of cytotoxicity.

[0021] In another aspect, the present invention provides therapeutic methods for treating subjects (e.g., vertebrates, such as humans) by modulating an immune response caused by increased expression of interleukins, the method comprising administering to the subject a therapeutically effective amount of an anti-CD6 antibody comprising SEQ ID NOs: 4 and 5 or a sequence having 98% identity thereto, including an antibody comprising SEQ ID NOs: 4 and 6 according to the present invention.

[0022] In another aspect, the present invention provides a kit for treating a subject for COVID-19 and variants thereof, wherein said kit comprises a therapeutically effective amount of an anti-CD6 antibody comprising or consisting of the amino acid sequence of SEQ ID NO: 4 (heavy chain) and 5 (light chain) or an amino acid sequence having 98% identity thereto, comprising or consisting of SEQ ID NO: 4 (heavy chain) and 6 (light chain) according to the present invention.

[0023] In a further aspect of the present invention, there is provided the manufacture of a medicament comprising an antibody to CD6, wherein the variable regions of the heavy and light chains comprise the amino acid sequences of SEQ ID NOs: 1 and 2, or an amino acid sequence of the variable regions having 98% identity thereto, comprising SEQ ID NOs: 1 and 3 according to the present invention.

[0024] In another aspect, the present invention provides the use of an anti-CD6 antibody comprising or consisting of the sequence of SEQ ID NO: 4 (heavy chain) and SEQ ID NO: 5 or SEQ ID NO: 6 (light chain) according to the present invention for the treatment of coronavirus, SARS and MERS-CoV, more particularly for the treatment of coronavirus COVID-19 infection in a subject, mammal or human.

[0025] In another aspect of the present invention, there is provided a method of treatment for use in a subject in need thereof, which comprises intravenous administration of a monoclonal antibody to CD6 in a dosage range of from about 0.5 mg/kg body weight to 8 mg/kg body weight, at least twice in two individual doses up to a maximum of 5 doses at an interval of 24 to 96 hours.

[0026] These and other advantages and features of the present invention will be more fully described in the detailed description of the preferred embodiments which follows.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[0027] Figure 1 shows the different stages of COVID-19 (SARS-Co V-2) disease, the first being an asymptomatic stage with or without detectable virus, stage 2 being a mild asymptomatic period with the presence of virus, and finally stage 3 being a severe symptomatic stage with high viral load and pulmonary edema.

[0028] Fig. 2 a) Remdesirvir; b) Galidesivir; c) Camostat; d) Fingolimod; e) Favipiravir; f) Darunavir/Cobicistat and Fig. 2 Continued: g) Chloroquine; h) Baricitinib; i) Thalidomide; j) Hydroxychloroquine; k) Rusolitinib; (i) Umifenovir represent prior art drugs in various clinical trials with their predicted mechanism of action.

[0029] Figure 3 shows the mean baseline IL-6 value, which was comparable in both groups, Figure 3A shows Group A, and Figure 3B shows Group B. After the first infusion, a significant decrease in mean IL-6 levels was observed in Group A.

[0030] Figure 4 shows the mean baseline TNFα value, which was comparable in both groups, Figure 4A shows group A, and Figure 4B shows group B. After the first infusion, a significant decrease in mean IL-6 levels was observed in group A.

[0031] Figure 5 shows the IL-6 concentration in the serum of COVID-19 patients before treatment with Itolizumab.

[0032] Fig. 6 shows a radiographic image of a patient with pneumonia caused by a bacterial infection. Fig. 6A) Before treatment with itolizumab and Fig. 6B) After treatment.

[0033] Figure 7 shows the decrease in mean C-reactive protein (CRP) concentration after the first dose of itolizumab. High CRP levels in COVID patients are associated with more severe disease (see, e.g., Liu et al. J Clin Virol. 2020 Jun; 127:104370).

[0034] Figure 8 shows the decrease in mean ferritin concentration after the first dose of Itolizumab. Ferritin is a key driver of immune dysregulation; it contributes to the cytokine storm and is a potential factor influencing the severity of COVID-19 (see, e.g., Vargas-Vargas M and Cortes-Rojo C. Ferritin levels and COVID-19. Rev Panam Salud Publica. 2020;44:e72).

[0035] Fig. 9 shows the percentage of patients who recovered from the disease and were treated with Itolizumab.

DETAILED DESCRIPTION OF THE INVENTION

[0036] It is known that COVID-19 and its variants can stimulate a cytokine storm in the lungs, such as increased levels of IL-2, IL-6, IL-7, GSCF, IP10, MCP1, macrophage inflammatory protein 1α (MIP1A), and TNFα, followed by edema, airflow dysfunction, acute respiratory distress syndrome, acute myocardial injury, and secondary infection, which may lead to death.

[0037] The terms "cytokine storm" and "cytokine release syndrome" are used to describe an exacerbation of the immune response in which there is excessive and uncontrolled release of proinflammatory cytokines. Cytokines are a group of small molecular weight proteins that act to mediate complex interactions between lymphoid cells, inflammatory cells, and hematopoietic cells. They have extremely diverse functions, which can nevertheless be classified into several distinct categories: differentiation and maturation of immune cells, communication between immune cells, and direct effector functions. Cytokines are produced during either the innate or adaptive immune response. They bind to specific receptors on the cell membrane where they exert their function by initiating a cascade of intracellular signaling that alters the gene expression profile so that target cells elicit a specific biological response.

[0038] Cytokines are produced by many types of cells, primarily by cells of the immune system. Among the most cytokine-producing cells in the innate immune system are macrophages, while helper T cells or T-CD4+ cells are the cells that primarily produce them in the adaptive or specific immune system. Cytokines are usually produced transiently, limited to the duration of the stimulus (i.e., the foreign agent that induces the immune response).

[0039] The patient's immune system works overtime to fight off the virus. Th1 cells become activated and release the cytokine IL6 and GM-CSF, as shown in Figure 1, which macrophages and neutrophils then transport to the alveoli of the lungs. These macrophages release more IL6, TNF-alpha, and IL1, among other pro-inflammatory cytokines. These cytokines cause fever by acting on the hypothalamus, as well as alveolar edema that clogs the lungs. At this point, the patient experiences difficulty breathing. The blood vessels around the alveoli become leaky and there is increased vascular permeability. Fluid loss causes circulatory stress and low blood pressure, which then leads to kidney failure and ultimately multiple organ failure.

[0040] There are currently no standard treatment options for COVID infection since it is a very new virus. However, several drugs are being tested based on the route of viral infection as mentioned above. Figure 2 shows drugs in various clinical trials with their predicted mechanism of action.

[0041] The present invention relates to a method for reducing morbidity in a patient infected with SARS-CoV-2, comprising administering to said patient a therapeutic amount of an anti-CD6 antibody. In certain embodiments, the anti-CD6 antibody is a monoclonal antibody. In some embodiments, the anti-CD6 antibody is the humanized monoclonal antibody itolizumab. In some embodiments, the anti-CD6 antibody is a Fab or fragment. In some embodiments, the patient has a bacterial infection. In some embodiments, the patient infected with SARS-CoV-2 has a comorbidity. In other embodiments, the patient infected with SARS-CoV-2 has more than one comorbidity. In some embodiments, the patient infected with SARS-CoV-2 has more than two comorbidities. In some embodiments, the patient infected with SARS-CoV-2 does not exhibit any mild or less than moderate symptoms. In some embodiments, the patient infected with SARS-CoV-2 exhibits moderate symptoms. In some embodiments, the patient infected with SARS-CoV-2 exhibits severe symptoms. In some embodiments, the patient infected with SARS-CoV-2 exhibits one or more symptoms of cytokine release syndrome (CRS). In some embodiments of the present invention, Itolizumab is administered to a patient who tests positive for COVID-19 and before the manifestation of one or more diseases. In some embodiments of the present invention, Itolizumab is administered to the patient in addition to one or more other therapeutic agents.

[0042] The antibody of the present invention binds to the leukocyte differentiation antigen CD6, which is a glycoprotein that is predominantly expressed on mature peripheral blood lymphocytes and to a lesser extent on mature B cells. It plays a critical role in lymphocyte adhesion, activation, differentiation and survival (Alonso, R et al. (2008) Hybridoma 27(4):291-301). The CD6 molecule contains three domains in its extracellular portion (Sarrias MR et al. (2004) Crit Rev Immunol. 24:1-37), and the binding site for its ligand, the ALCAM (activated leukocyte cell adhesion molecule), is located on domain 3 (Bodian DL et al. (1997) Biochemistry 36: 2637-2641). [0043] The humanized mAb itolizumab of the present invention recognizes and binds to the cysteine-rich domain 1 (D1) of the phagocytic receptor (SRCR) CD6 and does not interfere with the binding of CD6 to its ligand ALCAM, and therefore does not result in the immunosuppressive consequences reported in the context of other monoclonal antibodies used against the same target.

[0044] The use of CD6 antibodies, including non-depleting CD6 antibodies, as described in the present invention, rapidly alleviates the symptoms and signs associated with cytokine storm or cytokine release syndrome in treated patients. The reduction of these symptoms results in significant clinical improvement in critically ill patients and allows for improved patient management by the intensive care unit (ICU) team. A particular advantage of the proposed treatment is that it does not cause immunodeficiency in the patient, unlike other conventional steroid-based or other immunosuppressant-based treatments. Preservation of a certain degree of immunocompetence in treated patients reduces the possibility of emergencies due to other opportunistic infections that are very common in intensive care units.

[0045] The term "non-depleting" CD6 antibody, as used herein, means a monoclonal antibody specifically directed to CD6 that, when bound, does not induce antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cellular cytotoxicity (CDC), or otherwise promote lysis or death of a cell expressing CD6.

[0046] To date, there are no reports in the prior art on the use of anti-CD6 mAbs, in particular on the ability of these antibodies to inhibit the activation of the immune system and uncontrolled production of cytokines without causing immunodeficiency. The use of itolizumab is of great importance in combating the toxicity caused by the cytokine storm, which allows the body to continue to fight the viral infection caused by the coronavirus.

[0047] Unless otherwise indicated, all other scientific and technical terms used in the description, figures, and claims have their ordinary meanings commonly understood by one skilled in the art to which the invention pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice of testing the present invention, the preferred materials and methods are described herein. The following terminology will be used in the description and claims of the present invention.

[0048] It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used in the specification and the appended claims, the singular forms "a," "an," and "the" include a plurality of referents, except where the content clearly dictates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and the like.

[0049] The word "about" as used herein refers to a value that is within the range of acceptable error for a particular value as determined by one of skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" may mean within one or more standard deviations in accordance with practice in the art. The term "about" is also used to indicate that the quantity or value in question may be a stated value or some other value that is approximately the same. This language is intended to indicate that similar values provide equivalent results or effects disclosed herein. In this context, "about" may refer to a range up to 10% higher and/or lower. The word “about” in some embodiments refers to a range above and below a certain value that is up to 5%, such as up to 2%, up to 1%, or up to 0.5% above or below such value.

[0050] The term "activity," "biological activity," "therapeutic activity," or "functional activity" as used herein refers to the activity exhibited by itolizumab, as determined in vivo or in vitro, according to standard assays.

[0051] The term "effective antiviral amount" as used herein means an amount of the itolizumab compound of the invention that results in the treatment, prevention, slowing of the spread of coronavirus, including COVID-19, or manifestations of coronavirus, preventing infection of other persons, and/or improving the condition of a patient.

[0052] The term "cytokine" as used herein is intended to include any of a group of hormone-like mediators produced by T and B lymphocytes. Exemplary cytokines include, but are not limited to, interleukin-1 (IL-1), IL2, IL3, IL4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-18, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and transforming growth factor beta (TGF-beta).

[0053] The term "lymphocyte" as used herein has its ordinary meaning in the art and refers to any of the mononuclear, non-phagocytic leukocytes found in blood, lymph, and lymphoid tissues, such as B and T lymphocytes.

[0054] COVID-19 virus variants may include amino acid substitutions found in the viral spike protein as well as in the ORF protein region. For example, the B.1.1.7 variant has a signature mutation, N501Y. Other mutations, including A222V, E484K, S477N, and K417N/T, have been found to be more transmissible. As the virus spreads and more people become infected, additional variants are inevitable.

[0055] The terms "patient" and "subject" as used herein are used interchangeably and refer to human patients.

[0056] The terms "treating" or "treating" as used herein include administering the antibody compositions, compounds, or agents of the present invention to prevent or delay the onset of symptoms, complications, or biochemical indicators of a disease, to alleviate symptoms, or to stop or inhibit further progression of a disease, condition, or disorder (e.g., cancer, metastatic cancer, or metastatic breast cancer). The treatment may be prophylactic (to prevent or delay the onset of the disease, or to prevent the occurrence of its clinical or subclinical symptoms) or therapeutic suppression or alleviation of symptoms after the onset of the disease.

[0057] The term "well tolerated" as used herein refers to the absence of adverse changes in health status that occur as a result of treatment and that may influence treatment decisions.

[0058] The phrase "modulating an immune response" or "modulating an immune response" as used herein includes down-regulating, inhibiting, or reducing an immune response as defined herein. [0059] The term "anti-CD6 antibody" as used herein is an antibody that specifically binds to the SRCR domain 1 (D1) of human CD6 (hCD6) and that does not interfere with activated leukocyte cell adhesion molecule (ALCAM) binding to CD6.

[0060] The anti-CD6 mAbs (monoclonal antibodies) used herein can be administered as part of pharmaceutical compositions comprising the mAb as the active agent and, as a suitable excipient, a physiological buffer similar to that used to prepare mAbs intended for intravenous administration. In particular, itolizumab sequences are described in U.S. Patent Nos. 6,572,857 and 8,524,233, the contents of which are incorporated herein by reference in Table 1 below.

[0061] Table 1: Itolizumab protein sequence

[0062] Notably, CD6 is constitutively expressed primarily on effector T cells (Teff cells) and is rarely expressed on regulatory T cells (Treg). CD6 stimulates the immune response and is overexpressed following lymphocyte activation. CD6 guides inflammatory cells to the lesion, and its ligand ALCAM is up-regulated following activation and in inflamed tissues.

[0063] CD6 and viruses: CD6 is overexpressed on T cells during chronic simian immunodeficiency virus (SIV) infection with impaired antiviral response and is associated with SIV disease progression. Human T-lymphotropic virus type 1 (HTLV-1) induces ALCAM overexpression, facilitating the entry of infected lymphocytes across the blood-brain barrier. ALCAM is elevated on HIV+ monocytes, and ALCAM antibodies as well as a dual CCR2/CCR5 inhibitor reduce their transmigration.

[0064] Itolizumab is a humanized anti-CD6 IgG1 mAb. Itolizumab is an immunomodulatory molecule that does not deplete target cells (no cytopenia). Itolizumab accumulates at the site of inflammation. Itolizumab exerts potent anti-inflammatory activity by reducing the production of proinflammatory cytokines IL-6, TNF, IFNγ, IL-17, and IL-1.

[0065] This paper demonstrates that itolizumab has the ability to control pro-inflammatory cytokine storm syndrome in patients with COVID-19 by immunomodulating T _eff (Th1/Th2/Th17 cells) function and preventing lymphocyte trafficking to the site of inflammation (by disrupting ALCAM-CD6 interactions) without affecting Tregs and preserving the antiviral response. This is expected to reduce the morbidity and mortality associated with cytokine release syndrome in COVID-19 positive patients.

[0066] Notably, a higher percentage of CD14+ CD16+ inflammatory monocytes are present in the peripheral blood of COVID-19 patients. The percentage of CD14+ CD16+ monocytes is much higher in patients with ARDS manifestation. In addition, significantly higher IL-6 expression is secreted from these inflammatory monocytes, especially in ARDS patients. It is suggested that this increase in IL-6+ monocytes is due to the cytokine storm caused by monocytes that can migrate to the lung area. Thus, in COVID-19 patients, these activated immune cells may leak into the pulmonary circulation in large numbers and damage the immune system in ARDS. Thus, the present invention provides a new approach to reducing inflammatory cytokine proteins, which may include interleukins IL-1, IL-6 and IL-2 and interferon-gamma, and to treating patients with complications of hyperinflammation caused by COVID-19 and its variants.

[0067] In some embodiments, the methods of the present invention comprise preventing acute respiratory distress syndrome (ARDS) in a patient with COVID-19, wherein the method comprises treating the patient with a therapeutic amount of an anti-CD6 antibody. In some embodiments, the methods of the present invention reduce mortality due to ARDS in patients with COVID-19. In some embodiments, the present invention provides methods for reducing the length of hospital stay of a patient infected with SARS-CoV-2, wherein the method comprises administering to the patient a therapeutic amount of an anti-CD6 antibody. In some embodiments, the methods of the present invention prevent myocarditis in a patient with COVID-19. In some embodiments, the methods of the present invention are used to reduce mortality rates in the intensive care unit in patients with COVID-19.

[0068] In some embodiments, the methods of the present invention comprise preventing infectious diseases caused by bacterial agents in patients, wherein the method comprises treating the patient with a therapeutic amount of an anti-CD6 antibody. These bacterial agents include, but are not limited to, group A streptococci and pneumococci.

[0069] In some embodiments, itolizumab is administered to a patient in addition to one or more other therapeutic agents. In some embodiments, the additional therapeutic agent is selected from the group consisting of vaccines, antivirals, antibodies, immunotherapeutics, immune modulators, cytokine inhibitors, anticoagulants, complement inhibitors, microbiome regulators, and antimalarials. In some embodiments, the additional agent is a vaccine. In some embodiments, the vaccine is selected from the list consisting of BNT-162b2, ChAdOx1 nCoV-19, or mRNA-1273. In some embodiments, the additional agent is an antiviral agent. In some embodiments, the antiviral agent is selected from the list consisting of a viral neuraminidase inhibitor (e.g., oseltamivir or zanamivir), a viral polymerase inhibitor (e.g., ribavirin), or an M2 ion channel blocker (e.g., amantadine or rimantadine), remdesivir, biomedivir, favipiravir, or nanomedivir. In some embodiments, the additional therapeutic agent is a phase II inhibitor such as Toyama Chemical Co.'s T-705 (an oral polymerase inhibitor), Peramivir™, BioCryst (an iv/IM neuraminidase inhibitor), or a phase I inhibitor such as Biota/Daiichi Sankyo's CS-8958 (an inhaled neuraminidase inhibitor). In some embodiments, the additional agent is an antibody. In some embodiments, the additional agent is a neutralizing antibody. In some embodiments, the neutralizing antibody is LY-CoV555 or REGN-COV2. In some embodiments, the additional agent is an immunotherapeutic agent. In some embodiments, the additional agent is convalescent plasma. In some embodiments, the additional agent is an immunomodulator. In some embodiments, the immunomodulator is a glucocorticoid. In some embodiments, the immunomodulator is a kinase inhibitor. In some embodiments, the additional agent is ciclesonide. In some embodiments, the additional agent is baricitinib. In some embodiments, the additional agent is ruxolitinib. In some embodiments, the additional agent is a cytokine inhibitor. In some embodiments, the cytokine inhibitor is selected from the list consisting of tocilizumab, sarilumab, canakinumab, lenzilumab. In some embodiments, the additional agent is stem cell therapy. In some embodiments, the stem cell therapy is remestemcel-L or emiplacecel. In some embodiments, the additional agent is an anticoagulant. In some embodiments, the additional agent is an antithrombotic agent. In some embodiments, the methods of the present invention are used with an additional agent selected from the list consisting of rivaroxaban, sulodexide, apixaban, heparin, and aspirin. In some embodiments, the additional agent is a complement inhibitor. In some embodiments, the complement inhibitor is selected from eculizumab or ravulizumab. In some embodiments, the additional agent is a microbiome regulator. In some embodiments, the additional agent is EDP-1815. In some embodiments, the additional agent is an antimalarial agent. In some embodiments, the antimalarial agent is selected from chloroquine and hydroxychloroquine. In some embodiments, the present invention also includes antiviral compositions comprising an anti-CD6 antibody of the present invention administered with one or more other antiviral agents, such as reverse transcriptase (RT) inhibitors, nucleoside analogs, fusion inhibitors, and/or integrase inhibitors. In some embodiments, reverse transcriptase inhibitors include, but are not limited to, quevudine, telbivudine, tenofovir, dipoxyl, ganciclovir, lobucavir, famciclovir, and penciclovir. In some embodiments, nucleoside analogs include, but are not limited to, abacavir (ABC), adefovir (bis-POM PMEA), amdoxovir, apricitabine (AVX754), censavudine, didanosine (DDI), elvucitabine, emtricitabine (FTC), entecavir (ETV), lamivudine (3TC), racivir, stapudin, stavudine (d4T), tenofovir disoproxil (TDF), tenofovir alafenamide (GS-7340), zalcitabine (ddC), zidovudine (70U)/azidothymidine (AZT), derivatives thereof, optionally alkylated derivatives, also optionally trimethoxy-3TC, pharmaceutically acceptable salts thereof, and combinations thereof. In some embodiments, fusion inhibitors include, but are not limited to, enfuvirtide (Fuzeon), T-20, PRO 140, vicriviroc, and maraviroc. In other embodiments, integrase inhibitors include, but are not limited to, globoidnan A, L-000870812, S/GSK1349572, S/GSK1265744, Raltegravir, and Elvitegravir.

[0070] Therapeutic options for itolizumab for patients infected with COVID-19, including subjects with symptomatic or asymptomatic COVID-19 infections, are provided in Table 2.

[0071] Table 2: All options may also include azithromycin and antiretroviral drugs (anti-RNA polymerase).

[0072] The present invention includes prophylactic administration of itolizumab. The administration of itolizumab of the present invention can be performed before the onset of symptoms of the COVID-19 virus, such that the virus is prevented or, alternatively, its progression is delayed. The prophylactic methods of the present invention can be performed in analogy to the therapeutic methods described herein, although the dosing and treatment regimens may differ. Thus, it is believed that prophylactic administration of itolizumab as a preventive method in subjects who do not have evidence of the virus provides an advantage.

[0073] The present invention includes treatment or therapy of patients infected with COVID-19, including subjects with symptomatic or asymptomatic COVID-19 infections.

[0074] The monoclonal antibody itolizumab of the present invention is administered in a manner compatible with the dosage form and in an amount that will be therapeutically effective. The amount administered depends on the subject to be treated, the ability of the subject's immune system to generate a cellular immune response, and the desired degree of protection. The exact amount of active ingredient administered depends on the judgment of the attending physician and is individualized for each individual. However, itolizumab can be delivered in an effective amount of from about 0.1 to 25 mg/kg body weight per week, more preferably from about 0.5 mg/kg to about 10 mg/kg body weight, and most preferably from about 1 to 3 mg/kg body weight per week, delivered by intravenous (IV) administration. [0075] In one embodiment of the present invention, patients are screened for concomitant diseases and treated with a single dose of itolizumab. In one embodiment, COVID-19 patients with comorbidities are treated with 200 mg of itolizumab at a dose of 3.2 mg/kg. In one embodiment, the treatment is repeated after 1-14 days.

[0076] The combination compositions of the present invention may contain reduced doses of the active antiviral agent while maintaining the level of antiviral activity characteristic of a higher dose. As a result, the cytotoxicity normally associated with the administration of the antiviral agent is minimized by the administration of the combination compositions of the present invention. The combination compositions may contain a reduced dose of the antiviral agent in combination with itolizumab of the present invention to achieve a level of antiviral activity that is higher than normally required while maintaining an acceptable level of cytotoxicity.

[0077] Some methods of the present invention comprise first testing a patient for COVID-19, and for patients who test positive for COVID-19, administering a therapeutic dose of an anti-CD6 antibody. Some methods of the present invention include selection criteria for determining which patients with COVID-19 are to be treated with a therapeutic dose of itolizumab. Some methods of the present invention comprise testing for COVID-19 and assessing a patient for progression of lung injury and administering an anti-CD6 antibody to patients who test positive for COVID-19 and have progression of lung injury. In some methods of the present invention, determining whether the lung injury is progressing comprises assessing the patient to detect at least one of the following: a) worsening oxygen saturation; b) decreasing PaO ₂ ; c) need for increasing FiO ₂ ; d) unstable SO ₂ ; e) increased need for ventilator support; f) new need for ventilator support; f) increasing the number of consolidation areas and/or the degree of consolidation of the lungs. In some methods, oxygen saturation is deteriorated by more than 1 percentage point. In some methods of the present invention, oxygen saturation of the patient is deteriorated by >3 percentage points. In some embodiments, the decrease in _PaO2 is >10%.

[0078] In some embodiments, the methods of the present invention comprise selecting a patient with COVID-19 and suspected of having macrophage activation syndrome and administering a therapeutic dose of itolizumab. In some embodiments, a patient who tests positive for COVID-19 and requires oxygen therapy is administered a therapeutic dose of itolizumab. In some embodiments, the present invention consists of administering to a patient with COVID-19 with confirmed multifocal interstitial pneumonia a therapeutic dose of itolizumab. In some embodiments, a patient who tests positive for COVID-19 and also requires oxygen therapy to maintain _O2 saturation >93% is administered a therapeutic dose of an anti-CD6 antibody. In some embodiments, the methods of the present invention are used to treat a patient who tests positive for COVID-19 and has one or more of the following: a) wheezing or slurred speech; b) a respiratory rate greater than 22 breaths per minute; c) _PO2 : partial arterial pressure of oxygen <65 mmHg; d) worsening radiological image; e) fever >=38°C; f) decreased baseline values of hemoglobin, platelets, or neutrophils; g) Hb<90 g/L; h) platelets <100 ×109/L; i) neutrophils <1×109/L; j) leukocytes <4 ×109/L; k) decreased erythrocyte sedimentation rate inconsistent with PCR (low erythrocyte sedimentation rate and PCR increase or do not change); i) increased baseline value of triglycerides or triglycerides more than 3 mmol/L; m) increased baseline value of ferritin from 500 ng/mL or absolute value of ferritin >=2000 ng/mL; n) transaminase aspartate aminotransferase >=30 IU/L; a) increased D dimer; p) fibrinogen <2.5 g/L; q) occurrence of neurological manifestations. In some embodiments, the methods of the present invention include using exclusion criteria to select patients for treatment with an anti-CD6 antibody. In some embodiments, the exclusion criteria include one or more of the following: pregnancy, breastfeeding, and one or more adverse events.

[0079] Some embodiments of the present invention include determining how long to treat a patient and at what dose by measuring one or more primary efficacy criteria selected from the list consisting of the following: a decrease or deterioration in lung function, the frequency of patients who do not need to increase FiO ₂ to maintain SO ₂ stability and without the need for intubation; the frequency of patients with decreasing positive end-expiratory pressure (PPFE) values). In some embodiments, the measurement time of these criteria is from 1 to 7 days. Some embodiments of the present invention include determining how long to treat a patient and at what dose by measuring one or more secondary efficacy criteria selected from the list consisting of the following: 1. the need for endotracheal intubation; 2) an increase in the frequency of non-invasive or invasive mechanical ventilation when respiratory failure occurs; 3) an unfavorable outcome of non-invasive mechanical ventilation; 4) the duration of mechanical ventilation or the time until the end of mechanical ventilation; 5) the mortality rate of patients; 6) IL-1, IL-6 and TNF-alpha concentration in the patient's blood serum; 7) HSH diagnostic parameters (temperature, visceromegaly, cytopenia, triglycerides, fibrinogen, ferritin, AAT (GOT)); 8) C-reactive protein and absolute lymphocyte count (positive or negative).

[0080] Some methods of the invention comprise administering a therapeutic dose of an anti-CD6 antibody to a patient with moderate COVID-19. Some methods of the invention comprise administering a therapeutic dose of an anti-CD6 antibody to an elderly patient with COVID-19. In some embodiments, the patient is 64 years of age or older. In some embodiments, the anti-CD6 antibody is itolizumab. In some embodiments, hospitalized patients who test positive for COVID-19 are treated with itolizumab in combination with antiviral agents and compared to a control group that receives standard antiviral therapy without itolizumab. In some embodiments, patients are assessed for COVID-19 by real-time reverse transcription polymerase chain reaction (RT-PCR).

[0081] Statistical significance of treatment is determined by the mean and standard deviation or the median and interquartile ranges (depending on the distribution of each variable). The Wilcoxon rank sum test is applied to continuous variables, and the chi-square test or Fisher's exact test is used for categorical variables. In some embodiments, the present invention provides for the selection of a control group from the same group of hospitalized patients with COVID-19 who did not receive immunomodulatory therapy. The control group is treated with lopinavir/ritonavir, chloroquine, interferon α2B, and low molecular weight heparin (LMWH). Control subjects are matched for age, comorbidities, and disease severity. The hazard ratio of disease progression and mortality is estimated for itolizumab compared to control. Comorbidities include hypertension, dementia, malnutrition, heart disease, diabetes, and chronic obstructive pulmonary disease.

[0082] Each 5 mL vial contains 25 mg of itolizumab (r-DNA origin), which is a colorless, clear solution for intravenous infusion. Itolizumab is packaged in a 6R (USP Type 1) clear glass vial, closed with a chlorobutyl rubber stopper and sealed with a pull-off cap. Itolizumab for injection is a preservative-free solution supplied in single-use vials for intravenous infusion. Before use, the solution in the vial is visually inspected for particulate matter and color change. If visible opaque particles, discoloration, or other extraneous matter are observed, the vial should be discarded and the solution should not be administered to the patient. The appropriate volume of itolizumab injection was added to 250 mL of normal saline and mixed gently. This infusion bag containing diluted itolizumab can be stored at room temperature or refrigerated at 2°C to 8°C, protected from light, and is stable for up to 10 hours at room temperature. The infusion solution was allowed to reach room temperature before administration to patients. Itolizumab was infused over a period of at least 120 minutes using an infusion set with an in-line sterile, pyrogen-free, low protein-binding filter (pore size 1.2 μm or less). Approximately 50 mL of the infusion solution was administered over the first hour, followed by the remaining solution (approximately 200 mL) over the next hour. The infusion period may be extended to 8 hours if medically indicated. Itolizumab should not be co-administered with any other agents in the same catheter. Any unused portion of the infusion solution should not be stored for reuse.

[0083] Dosage regimens are adjusted to provide an optimal desired response (e.g., therapeutic response). For example, a single bolus may be administered, multiple divided doses may be administered over time, or the dose may be proportionally decreased or increased as required by the therapeutic situation. Effective doses and dosing regimens of the anti-CD6 monoclonal antibodies used in the present invention depend on the severity of the COVID-19 disease and its variants and can be determined by practicing physicians. In one embodiment, the anti-CD6 monoclonal antibody is administered by infusion at a weekly dose. Such administration may be repeated, for example, 1 to 8 times, such as 2 to 4 times, or 3 to 5 times. Alternatively, administration may be performed by continuous infusion over a period of 2 to 24 hours, such as 2 to 12 hours.

[0084] An exemplary, non-limiting range of a therapeutically effective amount of an anti-CD6 monoclonal antibody used in the present invention is about 0.01-100 mg/kg of subject body weight, such as about 0.01-50 mg/kg, such as about 0.01-25 mg/kg. In some embodiments, the ideal height-to-weight ratio of the patient is used to determine the dose. In some embodiments, the subject is administered more than one dose. In some embodiments, the patient is administered a higher initial dose. In some embodiments, the second dose is administered one week later. In some embodiments, the second dose is administered two weeks later. In some embodiments, the second dose has the same activity as the first dose. In some embodiments, the second dose is three-quarters or less of the initial dose. In some embodiments, the second dose is half of the initial dose. In some embodiments, a third treatment is administered. In some embodiments, therapeutically effective amounts of the monoclonal antibody to CD6 are administered every two weeks until the patient is determined to be recovering or discharged from the hospital. In some embodiments, the doses are either 0.8 mg/kg or 1.6 mg/kg. In some embodiments, the administered doses are 1.6 mg/kg and 0.8 mg/kg. Typical non-limiting doses of a therapeutically effective amount of the monoclonal antibody to CD6 used in the present invention are 0.8 mg/kg and 1.6 mg/kg. A healthcare professional having ordinary skill in the art can readily determine and prescribe the necessary effective amount of the pharmaceutical composition. For example, a physician can start with lower doses of the monoclonal antibody to CD6 than those needed to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0085] In one embodiment, the anti-CD6 monoclonal antibody is administered by infusion at a weekly dose of 0.1 to 50 mg/kg of the subject's body weight, such as 0.5 to 3 mg/kg. Such administration may be repeated, for example, 1 to 8 times, such as 2 to 4 times, or 3 to 5 times. Alternatively, administration may be by continuous infusion over a period of 2 to 24 hours, such as 2 to 12 hours. In one embodiment, the anti-CD6 monoclonal antibody is administered every week. In some of these embodiments, a dose of 50 mg to 350 mg of itolizumab is administered up to 7 times, such as 2 to 4 times. In some embodiments, the anti-CD6 antibody is administered once every two weeks. Administration may be by continuous infusion over a period of 2 to 24 hours, such as 2 to 12 hours. This regimen can be repeated one or more times as needed, for example, after one week or after two weeks.

[0086] Most study assessments and methods were conducted in accordance with the standard treatment protocols established by the participating study centres and the ICMR COVID-19 disease management guidelines. Treatment-emergent adverse events (TEAEs) were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) (v5.0) during treatment and within 30 days after the first treatment dose.

[0087] The examples that follow are set forth to assist in understanding the invention, but are not intended and should not be construed as limiting its scope in any way. The examples do not include a detailed description of the conventional methods used in the assay procedures. Such methods are well known to those skilled in the art and have been described in numerous publications, including in the form of examples.

[ 0088] Example 1

[0089] Patients with positive virological diagnosis of SARS-CoV2 infection (RT-PCR) were randomized for enrollment from various centers in India. [0090] The main inclusion criteria for patients were:

Confirmed virological diagnosis of SARS-CoV2 infection (RT-PCR).

Hospitalization due to clinical worsening of COVID-19 infection.

Oxygen saturation at rest in atmospheric air ≤94%.

Patients with moderate to severe acute respiratory distress syndrome, defined by a _PaO2 / _FiO2 (partial pressure of oxygen/fraction of inspired oxygen) ratio <200 or a deterioration of more than 25% from the immediate previous value.

Baseline serum ferritin ≥400 ng/mL or IL-6 levels greater than 4 times the upper limit of normal, if known.

[0091] The main exclusion criteria for patients were:

Presence of severe allergic reactions to monoclonal antibodies.

Active tuberculosis (TB) infection; Inappropriately treated TB or history of latent TB.

The patient is on invasive mechanical ventilation.

The patient has received oral antirejection drugs or immunosuppressants within the last 6 months.

Participation in other clinical trials of drugs, such as the use of anti-IL-6 therapies such as tocilizumab (participation in trials of antiviral agents against COVID-19 may be permitted if approved by the Sponsor).

The patient receives anti-IL-6 treatment or plasma therapy as maintenance therapy.

Pregnancy or breastfeeding, or a positive pregnancy test on pre-dose screening.

Patients with a history of hepatitis B, hepatitis C or HIV.

Absolute neutrophil count (ANC) <1000/ ^mm3 ; Platelet count <50,000/ ^mm3 ; Absolute lymphocyte count (ALK): <500/ ^mm3 .

[0092] A 6-week treatment study was conducted in two groups in approximately 36 patients.

[0093] Treatment Arm A: Best Supportive Care + Itolizumab (SEQ ID Nos: 4 and 5); in which best supportive care (e.g., antivirals/antibiotics/hydroxychloroquine; oxygen therapy, etc.) was administered together with itolizumab according to the institution's protocol. Patients in Arm A were premedicated with hydrocortisone 100 mg intravenously (or equivalent short-acting glucocorticoid) and pheniramine 30 mg intravenously for approximately 30±10 minutes prior to infusion.

[0094] Treatment Group B: Best supportive care, where: best supportive care, as per institutional protocol, was administered (e.g. antivirals/antibiotics/hydroxychloroquine, oxygen therapy, etc.) without itolizumab.

[0095] All eligible patients included in the study were randomized in a 2:1 ratio to receive Treatment A (best supportive care + itolizumab) or Treatment B (best supportive care), respectively. A computerized randomization schedule was generated using a suitable system, such as SAS software, to assign patients to treatment groups. Randomization was centralized, and remote telephone and computerized email systems were used to post the randomization schedule on site. If a patient was randomized to Group A and did not start itolizumab or did not receive one full infusion, the patient was not considered randomized. The same randomization code was used for the subsequent patient at that specific site.

[0096] Supportive care including oxygen therapy, heparin, antivirals, antibiotics, short-acting steroids and vitamins were allowed. Prior and concomitant treatment with oral anti-rejection drugs or immunosuppressants (continuous/regular within the last 6 months), anti-IL-6 therapy such as tocilizumab, convalescent plasma were not allowed.

[0097] Itolizumab injection is a preservative-free solution supplied in single-use vials for intravenous infusion. Prior to use, the solution in the vial was visually inspected for particulate matter and discoloration. If visible opaque particles, discoloration, or other foreign matter were observed, the vial was discarded and the solution was not administered to the patient. An appropriate volume of itolizumab injection was added to 250 mL of normal saline and mixed gently. This infusion bag containing reconstituted itolizumab can be stored at room temperature or refrigerated at 2°C to 8°C, protected from light, and is stable for up to 10 hours at room temperature. The infusion solution was allowed to equilibrate to room temperature prior to administration to patients.

[0098] Itolizumab was infused over a period of at least 120 minutes using an infusion set with an in-line sterile, pyrogen-free, low protein binding filter (pore size 1.2 μm or less). Approximately 50 mL of the infusion solution was administered over the first hour, followed by the remaining solution (approximately 200 mL) administered over the next hour. The infusion period may be extended to 8 hours if medically indicated. Itolizumab should not be co-administered in the same catheter with any other agents. Any unused portion of the infusion solution was not stored for reuse.

[0099] Most study assessments and methods were conducted in accordance with the standard treatment protocols established by the participating study centres and the ICMR COVID-19 disease management guidelines. Treatment-emergent adverse events (TEAEs) were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) (v5.0) during treatment and up to 30 days after the first treatment dose.

[00100] As noted above, a total of 36 patients were screened, of whom 4 patients failed screening. Of the 32 patients who met inclusion criteria or did not meet exclusion criteria, 2 patients who were to be treated with itolizumab discontinued treatment before completion of the first dose and were replaced according to the protocol. The median age of patients in Arm A was 50.5 years and 49.5 years in Arm B. Most were male in both treatment groups and all patients were Asian. All patients in Arm A and the majority of patients in Arm B (all surviving patients) completed the study; this included 16 (80%) and 6 (60%) patients in Arms A and B, respectively, who discontinued the clinical trial early. The most common reason for study discontinuation in Arm B was death (n=3). There were no deaths in Arm A. Patients in Group A received best supportive care plus itolizumab 1.6 mg/kg for two weeks; patients in Group B received best supportive care alone.

[00101] Itolizumab treatment significantly improved patient survival by reducing the 1-month mortality rate. A statistically significant difference (p=0.0098) in 1-month mortality was observed between treatment groups A and B. All patients receiving the itolizumab dose consistently demonstrated improvement in lung function parameters:

• Significantly stable/improved oxygen saturation ( _SpO2 ) and _PaO2 without increase in _FiO2 .

• _O2 requirements decreased after dosing.

• PaO ₂ /FiO ₂ ratio improved consistently in all patients.

Overall, a higher proportion of patients in Group A had stable/improved SpO ₂ without increasing FiO ₂ . Overall, a higher proportion of patients in Group A had stable PaO ₂ without increasing FiO ₂ at all post-baseline assessment visits. A statistically significant difference was observed between both treatment groups for both parameters from day 21 onwards.

• PFR (PaO ₂ /FiO ₂ ratio) gradually increased over time in groups A and B. The mean PFR was 350.25 in group A and 398.33 in group B at 21 days.

• Biomarkers such as IL-6, IL-17A and TNF-α showed a decrease after treatment with itolizumab. Patients demonstrated a greater reduction in mean change from baseline levels compared to the control group.

IL-6 is a proinflammatory cytokine. As can be seen in Fig. 3, the mean baseline IL-6 value was comparable in both groups; 159.1 pg/mL in Group A and 162.2 pg/mL in Group B. A significant decrease (p=0.0269) in the mean IL-6 levels after the first infusion was observed in Group A (43 pg/mL) compared to Group B (212 pg/mL). The p-value was assessed using the Wilcoxon signed-rank test for matched pairs. TNF-α is a proinflammatory cytokine. As can be seen in Fig. 4, the mean baseline TNF-α value was higher in Group A (44 pg/mL) than in Group B (11 pg/mL). A significant decrease (p=0.0253) in mean TNF-α levels after the first infusion was observed in group A (9 pg/mL) compared to an increase in group B (39 pg/mL). TNF-α levels before the second dose were 68 pg/mL and 108 pg/mL in groups A and B, respectively. After the second dose, a decrease in TNF-α levels was also observed in group A (50 pg/mL) compared to an increase in group B (185 pg/mL). P-value was assessed using the Wilcoxon signed-rank test for matched pairs.

IL-17A is a proinflammatory cytokine. The mean baseline IL-17A was comparable in both groups; 10.36 pg/mL in group A and 9.83 pg/mL in group B. A marked decrease in mean IL-17A levels after the first infusion was observed in group A (6.75 pg/mL), compared to an increase in group B (14.75 pg/mL). A slight decrease in IL-17A levels was also observed after the second dose in group A compared to an increase in group B.

• Other important markers of organ dysfunction and coagulopathy, such as LDH (lactate dehydrogenase) and D-dimer, also showed a more significant mean decrease in group A compared to the control group.

[00102] The primary endpoint of mortality was highly statistically significant in favor of the itolizumab group; p-value=0.0098. Itolizumab consistently demonstrated improvement in lung function parameters and reduction in inflammatory biomarkers. Itolizumab was safe for patients with COVID-19. Infusion reactions were managed by reducing the infusion rate. Itolizumab effectively controlled the hyperactivation of the immune system in response to the COVID-19 virus and reduced cytokine storm-related morbidity and mortality.

[00103] Overall, itolizumab treatment was well tolerated in patients with COVID-19 along with BSC (best supportive care), with no new safety concerns arising from the therapy.

[00104] Example 2. Itolizumab (SEQ ID No: 4 and 6) reduced mortality in severely ill and critically ill patients.

[00105] Forty-eight patients diagnosed with SARS-CoV-2 or with high clinical suspicion of COVID-19 pneumonia and clinical, radiographic, or laboratory evidence of cytokine release syndrome were administered a 200 mg dose of the monoclonal antibody itolizumab intravenously. Of these, 22 patients (14 critically ill and 8 severely ill) received a second dose of the antibody after 72 hours, and 3 critically ill patients received a third dose because they had persistent signs of respiratory failure or macrophage activation syndrome. To assess the impact of using this product in the studies, each COVID-19 positive patient with recovery or death information registered with the Ministry of Health, with at least one comorbidity in history considered a risk factor for severe/fatal outcome of COVID-19 (hypertension, coronary heart disease, diabetes mellitus, cancer, chronic kidney disease, obesity, malnutrition or COPD) or who was hospitalized in the intensive care unit in the country and who was not included in any of the ongoing COVID-19 clinical trials, was selected as a control. The χ ² test was used for statistical processing of the data.

[00106] As shown in Table 3, the mortality rate of patients receiving itolizumab was 15% lower than that of the control group. In addition, the mortality rate of severely ill patients receiving itolizumab was significantly lower than that of severely ill patients in the control group.

[00107] Table 3: Mortality of seriously ill or critically ill patients

[00108] Example 3: Itolizumab reduced mortality in patients with moderate disease at high risk of progression to severe or critical disease.

[00109] A sample of 14 patients with moderate disease severity, with 2 or more comorbidities predicting mortality, were administered 200 mg [at a dose of 3.2 mg/kg body weight] of the monoclonal antibody itolizumab (SEQ ID Nos: 4 and 6) intravenously. Patients who were not diagnosed during their stay in the intensive care unit and who had 2 or more comorbidities were selected as an untreated control group. The χ ² test was used for statistical analysis of the data.

[00110] As can be seen in Table 4, the mortality rate of patients with a high risk of the disease progressing to severe or critical stage decreased by 27%.

[00111] Table 4: Mortality rate of patients with moderate disease

[00112] Example 4. Treatment with itolizumab reduced serum IL-6 concentrations in critically and severely ill COVID-19 patients and stabilized such levels in patients with moderate disease.

[00113] In 21 COVID-19-positive patients treated with the monoclonal antibody itolizumab (SEQ ID Nos: 4 and 6), serum IL-6 concentration levels were determined using ELISA (Quantikine) at baseline and 48 hours after administration. Patients were classified as moderately ill: n=12; severely ill: n=4; and critically ill: n=5.

[00114] As shown in Fig. 5, before initiation of itolizumab treatment, IL-6 levels in patients increased with disease progression. Serum concentrations in critically ill patients were significantly higher than in patients with moderate disease (Kruskal-Wallis test; p=0.0015). Baseline IL-6 levels were associated with disease severity using a ROC curve, with a cutoff value of 27.4 pg/mL for serum IL-6.

[00115] In a group of 16 patients receiving itolizumab, serum IL-6 concentrations were assessed before the first administration and 48 hours after. Table 5 shows the change in IL-6 values after 48 hours depending on the established cutoff value.

[00116] In all patients with circulating IL-6 levels above 27.4 pg/mL, values were reduced by a single dose of itolizumab, with measurements taken 24-48 hours after administration. The magnitude of the change in IL-6 concentration among patients with concentrations above the cutoff was a mean decrease of 50.9 pg/mL. However, the mean change in IL-6 concentration among patients with baseline levels below 27.4 pg/mL was 1.5 pg/mL.

[00117] Table 5: Change in IL-6 values after 48 hours as a function of the cutoff value that discriminates disease severity

[00118] Example 5. Clinical improvement in a critically ill patient with cytokine storm caused by a respiratory infection of bacterial origin who received itolizumab.

[00119] A female patient diagnosed with community-acquired bronchopneumonia (Figure 6A) with a guarded prognosis and who was a heavy smoker with bronchial asthma received an intravenous dose of approximately 200 mg of the mAb itolizumab (SEQ ID Nos: 4 and 6). Her vital signs on admission were temperature 38.2°C, respiratory rate 120 and pulse rate 89, BP 90/60, saturation _0.2 98, _P0 2.116, _P0 2.88, creatinine 50, hematocrit 0.32, leukogram 16.5 × 10 ⁹ , lymphocytes 0.24 and monocytes 0.02, platelets 350 × 10 ⁹ , parameters that suggested the patient had a cytokine storm. In addition to mAb, she received concomitant treatment with meropenem and vancomycin, gentamicin, oseltamivir, omeprazole, flaxieheparin, morphine, midazolam, vitamin therapy, chlorhexidine 0.1% for mouthwash.

[00120] There was positive dynamics in the radiographic examinations after 48 hours, as well as a significant improvement in vital parameters (Figure 6B). Axial computed tomography examination performed ten days after the administration of the antibody showed no evidence of interstitial pneumonia, only calcified nodules at the base of the lungs, which are commonly found in heavy smokers such as this patient. In addition, no adverse events related to the administration of the antibody were reported. There were no subsequent infections. Fourteen days after admission, the patient was discharged for medical reasons.

[00121] Example 6. Itolizumab treatment demonstrated a high recovery rate in patients with suspected COVID-19 not confirmed by PCR.

[00122] A total of 22 patients admitted to Roberto Rodriguez Hospital (Moron, Ciego de Avila) with clinically suspected COVID-19 pneumonia (not confirmed by PCR) received a 200 mg dose of itolizumab (SEQ ID Nos: 4 and 6) intravenously and two doses of the antibody in one case. Patients were in critical, severe or moderate condition with a high risk of exacerbation upon hospital admission. The concentration of inflammatory parameters was determined before antibody administration and 48 hours after administration. The mean values of C-reactive protein (Figure 7) and ferritin (Figure 8) concentrations decreased 48 hours after treatment, indicating that itolizumab treatment caused a decrease in markers associated with severe COVID disease and/or cytokine storm. In Fig. 9 showed that despite the high levels of inflammation observed prior to antibody administration, recovery occurred in all moderate and severely ill patients and in 86% of all treated patients.

[00123] Example 7. Treatment of COVID-19 patients requiring hospitalization

[00124] The study included adult men or women aged 18 years or older with a confirmed virologic diagnosis of SARS-CoV-2 infection by RT-PCR and the need for hospitalization due to clinical worsening of COVID-19 infection with resting oxygen saturation in ambient air <94%. Patients with moderate to severe ARDS defined by a _PaO2 / _FiO2 ratio <200 or a worsening of more than 25% compared to the immediate previous value and patients with baseline serum ferritin ≥400 ng/mL or IL-6 levels greater than 4 times the upper limit of normal (ULN) were included.

[00125] The first dose of itolizumab (SEQ ID NOS: 4 and 6) was 1.6 mg/kg. In vitro CD6 receptor occupancy was assessed and the 1.6 mg/kg dose demonstrated 99% receptor occupancy. Some patients were given an additional 0.8 mg/kg dose after 1 week as needed. Because patients had varying degrees of host inflammatory response, not all patients required subsequent weekly doses. The decision was left to the discretion of the investigator based on clinical status and inflammatory markers. The study allowed for up to four doses per week.

[00126] Example 8. Treatment of COVID-19 patients before the onset of cytokine storm symptoms

[00127] The first dose of itolizumab (SEQ ID NOs. 4 and 6) was administered at 1.6 mg/kg. This 1.6 mg/kg loading dose was chosen because it is the approved dose for patients with chronic plaque psoriasis, and doses up to 1.6 mg/kg have been administered by intravenous infusion in multiple Phase 2 and 3 clinical trials with no evidence of dose-limiting toxicity. Because itolizumab is an anti-CD6 antibody, CD6 receptor occupancy was assessed in vitro, and because the 1.6 mg/kg dose demonstrated 99% receptor occupancy, it was chosen as the first dose. Some patients received an additional 0.8 mg/kg dose 1 week later as needed. Because patients had varying degrees of host inflammatory response, not all patients required subsequent weekly doses. The decision was made by the investigator based on clinical status and inflammatory markers. The study allowed up to four doses per week.

[00128] Example 9. Treatment of hospitalized patients with COVID-19 with itolizumab

Twenty subjects with COVID-19 receiving standard of care were given an intravenous infusion of itolizumab (SEQ ID NOs: 4 and 6) at an initial dose of 1.6 mg/kg. Subjects with no or mild adverse effects from the initial dose who continued to experience COVID-19 symptoms were given an additional 1.6 mg/kg every two weeks. Six subjects received a single dose of itolizumab at 1.6 mg/kg; seven subjects received two doses of 1.6 mg/kg with an interval of two weeks between doses; three subjects received a single dose of itolizumab at 1.6 mg/kg, followed by a dose of 0.8 mg/kg one week later, and a final dose of itolizumab at 0.8 mg/kg one week later; Four subjects received a single dose of itolizumab 1.6 mg/kg, and over the next three weeks they received three additional doses of 0.8 mg/kg with a one-week interval between each dose, for a total of four treatment doses.

[00129] Example 10. Treatment of patients with COVID-19 with itolizumab or placebo in addition to standard therapy

Patients with COVID-19 are divided into two groups, one of which receives standard therapy plus placebo, and the other receives an intravenous infusion of itolizumab at an initial dose of 1.6 mg/kg (based on ideal body weight) in addition to the standard. On day 8, patients in the treatment group receive an additional 0.8 mg/kg if they: - a) were not discharged from the hospital; b) did not recover in hospital; c) did not have anaphylaxis with the first dose; d) do not have an ALC of 0.5; and d) are not diagnosed with active tuberculosis.

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SEQUENCE LIST

<110> Biocon Limited

<120> ANTI-CD6 ANTIBODY COMPOSITIONS AND METHODS FOR TREATING AND

REDUCING NEGATIVE EFFECTS OF A CORONVIRUS INCLUDING COVID-19

<130> 650-1009

<150> 202041014994

<151> 2020-04-04

<150> 2020-0027

<151> 2020-04-17

<160> 6

<170> PatentIn version 3.5

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<---

Claims (17)

1. Use of a non-depleting CD6 antibody that specifically binds to domain 1 of CD6 for the treatment of an infectious disease that results in a cytokine storm or cytokine release syndrome, wherein said non-depleting CD6 antibody comprises the amino acid sequences set forth in SEQ ID NOs: 1 and 2, or a non-depleting CD6 antibody that specifically binds to domain 1 of CD6 has 98% identity to SEQ ID NOs: 1 and 2. 2. The use of a non-depleting CD6 antibody according to claim 1, wherein the infectious diseases are caused by pathogens selected from the group consisting of: coronavirus, group A streptococci and pneumococci. 3. Use of a non-depleting CD6 antibody that specifically binds to domain 1 of CD6 for the treatment of an infectious disease caused by a coronavirus that results in a cytokine storm or cytokine release syndrome, wherein said non-depleting CD6 antibody comprises the amino acid sequences set forth in SEQ ID NOs: 1 and 2, or a non-depleting CD6 antibody that specifically binds to domain 1 of CD6 has 98% identity to SEQ ID NOs: 1 and 2. 4. The use according to paragraph 3, where the coronavirus is the SARS coronavirus, MERS-CoV or SARS-CoV-2 and their variants. 5. The use according to claim 1, wherein said non-depleting antibody to CD6, which specifically binds to domain 1 of CD6 and has 98% identity with SEQ ID NO: 1 and 2, comprises SEQ ID NO: 1 and SEQ ID NO: 3. 6. Use of an anti-CD6 antibody that specifically binds to domain 1 of CD6 for the treatment of COVID-19, wherein said anti-CD6 antibody reduces cytokine expression and comprises the amino acid sequences set forth in SEQ ID NOs: 4 and 5, or an anti-CD6 antibody that specifically binds to domain 1 of CD6 has 98% identity to SEQ ID NOs: 4 and 5. 7. The use according to claim 6, wherein said antibody to CD6, which specifically binds to domain 1 of CD6 and has 98% identity with SEQ ID NO: 4 and 5, comprises SEQ ID NO: 4 and SEQ ID NO: 6. 8. The use according to any of the preceding claims, wherein said CD6 antibody is in an effective amount of from 0.5 mg/kg body weight to 10 mg/kg body weight. 9. A method of treating a subject infected with a coronavirus, comprising treating with a therapeutically effective amount of an anti-CD6 antibody comprising the amino acid sequences set forth in SEQ ID NOs: 4 and 5, or an amino acid sequence having at least 98% identity thereto comprising SEQ ID NOs: 4 and 6, wherein said anti-CD6 antibody reduces high levels of expression of cytokines produced during a cytokine storm. 10. The method according to claim 9, wherein the coronavirus is SARS, MERS-CoV or SARS-CoV-2 coronavirus. 11. A method of treating a subject infected with bacteria, comprising treating with a therapeutically effective amount of an anti-CD6 antibody comprising the amino acid sequences set forth in SEQ ID NOs: 4 and 5, or an amino acid sequence having at least 98% identity thereto comprising SEQ ID NOs: 4 and 6, wherein said anti-CD6 antibody reduces high levels of expression of cytokines produced during a cytokine storm, wherein said bacteria are selected from the group consisting of: group A streptococci and pneumococci. 12. The method according to any one of claims 9-11, wherein the therapeutically effective amount of the antibody to CD6 is from 0.5 mg/kg body weight to 10 mg/kg body weight. 13. The method of claim 12, wherein the CD6 antibody is administered to the subject at least twice, wherein the time between two consecutive administrations is from 24 to 96 hours. 14. A kit for treating a subject for COVID-19, wherein said kit comprises a therapeutically effective amount of an antibody to CD6 consisting of the amino acid sequence of SEQ ID NOs: 4 and 5 or an amino acid sequence having 98% identity thereto consisting of SEQ ID NOs: 4 and 6. 15. A method of treating a subject infected with a coronavirus, comprising treatment with a therapeutically effective amount of an anti-CD6 antibody comprising the amino acid sequences set forth in SEQ ID NOs: 4 and 6, wherein C-reactive protein and ferritin concentrations are reduced within 48 hours of initiation of treatment. 16. The use according to any one of claims 1-8 or the method according to any one of claims 9-13, 15, wherein the antibody to CD6 is a humanized monoclonal IgG1 antibody. 17. The use or method according to claim 16, wherein said CD6 antibody is itolizumab.