WO2021260692A1 - Compositions and methods for treating infectious disease caused by coronavirus - Google Patents
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1002—Coronaviridae
- C07K16/1003—Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2 or Covid-19]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Definitions
- compositions comprising human polyclonal antibodies and methods of using same for treating or preventing coronavirus infections and diseases, disorders and symptoms associated with coronavirus infection.
- Coronaviruses are enveloped, positive-sense single-stranded RNA viruses. They have the largest genomes (26-32 kb) among known RNA viruses, and are phylogenetically divided into four genera (alpha, beta, gamma, delta), with beta-coronaviruses further subdivided into four lineages (A, B, C, D). Coronaviruses infect a wide range of avian and mammalian species, including humans.
- HCoV- OC43 HCoV-229E
- HCoV-HKUl HCoV-NL63
- HCoV-NL63 HCoV-NL63
- MERS-CoV Middle East respiratory syndrome coronavirus
- SARS-CoV severe acute respiratory syndrome coronavirus
- SARS-CoV-2 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus induced disease 19 (CQVID-19) that emerged in China in late 2019 and became the cause of a pandemic. As of October 2020, over 48M cases have been reported worldwide, of whom an estimated 2% succumbed to the infection. SARS-CoV-2 belongs to the Sarbecovirus subgenus (genus Betacoronavirus, family Coronaviridae), as does the SARS-CoV that emerged in 2002 and caused -8,000 infections with a lethality of 10%. Both viruses can cause a life-threatening respiratory illness in humans.
- Remdesivir (Veklury®) was approved in the US for hospitalized patients with COVID-19, but has only shown a modest benefit. Dexamethasone is also recommended by the NTH for patients who are ventilated or in need of supplemental oxygen. [0004] The high infection rate, vaguely defined epidemiology, and absence of prophylactic or therapeutic measures against coronaviruses have created an urgent need for effective preventive and therapeutic agents.
- compositions comprising anti-coronavirus human polyclonal antibodies and use thereof for treating and preventing COVID-19 and symptoms associated therewith.
- COVID-19 as used herein is interchangeable with the terms “coronavirus disease”, “COVID-19 disease”, and further refers to diseases, disorders, and symptoms associated with the COVID-19 infection.
- treating or preventing coronavirus infection by using the human polyclonal antibodies disclosed herein is advantageous over the use of whole plasma derived from convalescent donors from a safety perspective, as the purification methods used for obtaining the human polyclonal antibodies minimizes known and potentially severe side effects, such as, transfusion reactions, allergic reactions to plasma contents, ABO incompatibility, and potential exposure to HBV, HCV and HIV among others viruses.
- the latter may be life-threatening to patients suffering from heart failure, which is one of the common disorders associated with coronavirus infection. It is well known that the increase in fluid volume increases the burden on the weakened heart, further exacerbating the problem. Moreover, delivery of large volumes must be carried out by intravenous infusion, while delivery of a small volume, below 100 ml, can be performed via more comfortable routes of administration, including, but not limited to, intravenous infusion, subcutaneously, intraperitoneally (i.p.) and i.v. injection, which are fast, cost effective and altogether enable more convenient routes of administration, which altogether provide improved compliance. Compliance is important in ensuring an improved health outcome for the patients, especially those suffering from a chronic condition and/or requiring prolonged medical attention.
- the anti-SARS CoV-2 antibodies disclosed herein provides an effective treatment not only against the SARS CoV-2 wild type, but also against variants thereof, including, but not limited to, the South African and the British variants.
- a method for treating COVID- 19 disease in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising anti-coronavirus human polyclonal antibodies.
- said treating COVID-19 comprises treating disease or disorders associated with COVID-19.
- the disease or disorders associated with COVID-19 comprise influenza, tracheitis and pneumonia.
- the anti-coronavirus human polyclonal IgG comprise anti-coronavirus human polyclonal IgGl, anti-coronavirus human polyclonal IgG2 and anti-coronavirus human polyclonal IgG3.
- the anti-coronavirus human polyclonal IgG is devoid of anti-coronavirus human polyclonal IgG4.
- the anti- coronavirus human polyclonal IgG has low amounts of anti-coronavirus human polyclonal IgG4, relative to the amounts of anti-coronavirus human polyclonal IgGl-3.
- the anti-coronavirus human polyclonal antibodies comprise trace amounts of IgM and IgA. According to some embodiments, the anti-coronavirus human polyclonal antibodies comprise negligible amounts of IgM and IgA. According to some embodiments, the anti-coronavirus human polyclonal antibodies comprise low amounts of IgM and IgA relative to the amounts of IgG.
- the anti-coronavirus human polyclonal antibodies are derived from the plasma of convalescent human donors. According to some embodiments, the anti-coronavirus human polyclonal antibodies are derived from the plasma of convalescent vaccinated human donors. According to some embodiments, the anti-coronavirus human polyclonal antibodies are derived from the plasma of vaccinated human donors.
- the COVID-19 disease comprises pneumonia. According to some embodiments, the COVID-19 disease comprises tracheitis. According to some embodiments, the COVID-19 disease comprises influenza.
- the pharmaceutical composition is in a liquid form.
- the anti-coronavirus human polyclonal antibodies have a binding capacity to coronavirus, or to antigen associated therewith, which is at least 6- fold higher than the binding capacity of negative plasma samples derived from one or more human donors who were not infected by coronavirus and/or do not have antibodies to determinants associated with coronavirus.
- said administering comprises at least one administration. According to some embodiments, said administering comprises a plurality of administration.
- said treatment is prophylactic treatment.
- said subject in need thereof is a healthy subject and the treatment is prophylactic.
- the subject in need thereof is a subject afflicted with COVID-19, having mild symptoms, and the treatment is prophylactic, aimed to prevent hospitalization, and/or to prevent exacerbation of COVID-19.
- composition comprising anti-coronavirus human polyclonal antibodies method for the treatment of COVID- 19 disease.
- the pharmaceutical composition is in a liquid form.
- the pharmaceutical composition is for intravenous use.
- said treatment is prophylactic treatment.
- Fig. 1A demonstrates preliminary results of the IgG titer from four main manufacturing process steps: sample (62201) is filtrated plasma pool taken from convalescent donors, sample (63301) is the diluted sample post DEAE column with IgG purification of >95%, DS is the concentrated Drug Substance and DP is the final drug product. Anti SARS- CoV-2 IgG content is expressed as fold positive binding assay results.
- Fig. 4A represents PRNT neutralization results.
- Fig. 4B represents the high correlation between anti SARS COV-2 IgG concentration determined by ELISA and the neutralization activity.
- Fig. 5 represents the end point titer of the drug product.
- Fig. 7 represents the various IgG subclasses in the drug product.
- SARS-CoV-2 is a Human Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) immune gamma globulin preparation that is manufactured from convalescent plasma of COVID- 19 recovered patients, using suitable purification methods, as disclosed herein.
- SARS-CoV-2 Human Severe Acute Respiratory Syndrome Corona Virus 2
- Purified immunoglobulins from convalescent plasma are expected to be superior to plasma as they are pooled from a large antibody repertoire, eliminate the need for donor and recipient matching, reduce the risk for blood-borne infectious agents, have a lower volume, and do not require freezing and thawing.
- coronavirus as used herein, includes, but is not limited to, anyone or more of SARS-CoV-2, MERS-CoV, SARS-CoV, NL63-CoV, 229E-CoV, OC43-CoV, HKUl-CoV, WIVl-CoV, MHV, HKU9-CoV, PEDV-CoV, and SDCV. Furthermore, this term includes variants of SARS-CoV-2, such as, the British/UK variant (B.1.1.7) also known as the alpha variant and the South African variant, also known as beta variant (B.1.351). It is note that viruses constantly change through mutation, where a variant has one or more mutations that differentiate it from other variants in circulation.
- the B.1.1.7 (Alpha), B.1.351 (Beta), P.l (Gamma), B.1.427 (Epsilon), B.1.429 (Epsilon), and B.1.617.2 (Delta) variants circulate in the United States and are classified as variants of concern. Accordingly, it has been suggested that specific monoclonal antibody treatments may be less effective for treating cases of COVID- 19 caused by variants.
- a report from South Korea describes three patients with MERS who were treated with convalescent plasma, but only two of the recipients demonstrated neutralizing antibodies in their plasma.
- the latter study highlights a challenge in using convalescent plasma, namely, that some individuals who recover from a viral disease may not have high titers of neutralizing antibodies.
- an analysis of 99 samples of convalescent sera from patients with MERS showed that 87 of them had neutralizing antibodies with a geometric mean titer of 1:61. This suggests that antibody levels decline with time and/or that few patients demonstrate high titer responses.
- antibodies derived from convalescent plasma are not necessarily effective therapeutically.
- a general principle of passive immunization therapy is that it is most effective when administered shortly after the onset of symptoms.
- the reason for the temporal variation in efficacy is not well understood but could reflect the observation that passive immunization works by neutralizing the initial inoculum, which is likely to be much smaller than the viral load seen in established disease following viral spread.
- Another explanation is that antibodies work by modifying the modest inflammatory response observed during the initial phase of the disease, which maybe asymptomatic.
- passive immunization therapy for pneumococcal pneumonia was found to be most effective when administered shortly after the onset of symptoms and there was no benefit if antibody administration was delayed past the third day of disease.
- Convalescent plasma (CP) therapy has several limitations.
- CP infusions can transmit blood-borne infections, and induce febrile and allergic transfusion reactions, anaphylaxis in IgA-deficient recipients, transfusion-associated circulatory overload, and transfusion-related acute lung injury.
- variability between plasma units e.g., variation of antibody specificity, affinity, and concentration.
- a gamma globulin therapy using the purified anti-coronavirus human polyclonal antibodies disclosed herein beneficially circumvents the limitations of CP.
- the disclosed anti-coronavirus human polyclonal antibodies are produced from multiple donors, which are pooled.
- the gamma globulins are then highly purified, and aliquoted into injectable doses, which are standardized for antibody characteristics.
- the resulting gamma globulin composition has batch-to- batch consistency, provides higher concentrations of antibodies that can be readily given as a small- volume, preferably intravenously, and has less risk of causing serious transfusion-related adverse events (e.g., blood borne pathogen transmission, transfusion reactions).
- production of the highly purified immunoglobulins is scalable and the resulting products can be stored refrigerated for prolonged durations without the need to freeze the sample, as is the case with plasma samples. This provides a practical approach for disseminating this treatment widely.
- an “antibody” refers to a polypeptide substantially encoded by an immunoglobulin gene(s), which recognizes an epitope (antigen), and has the ability to bind thereto.
- the recognized immunoglobulin encoding genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes.
- An exemplary immunoglobulin (antibody) structural unit is composed of two pairs of polypeptide chains, each pair having one "light” (about 25 kD) and one "heavy" chain (about 50-70 kD).
- each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
- VL variable light chain
- VH variable heavy chain
- the immunoglobulin will consist of an immunoglobulin preparation isolated from pooled plasma (preferably human plasma) comprising IgG immunoglobulins.
- the light chains are commonly classified as kappa or lambda and the heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD, and IgE, respectively.
- Immunoglobulins can be produced from the plasma of unselected donors, while the anti-coronavirus immunoglobulins disclosed herein were produced from the plasma of donors with high antibody titers against the receptor binding domain (RBD) of the S 1 protein of the SARS CoV-, in a process that included meticulous screening steps of the plasma, as detailed below.
- the anti-coronavirus immunoglobulins are derived from convalescent donors.
- the convalescent donors are donors identified during the convalescent period after infection.
- the anti-coronavirus immunoglobulins are derived from donors specifically vaccinated.
- polyclonal antibodies are used herein denotes a mixture of different antibody molecules that react with more than one immunogenic determinant of an antigen.
- polyclonal antibodies encompasses polyclonal antibodies preparation isolated or purified from human blood, serum or plasma, namely, human polyclonal antibodies.
- human polyclonal antibodies refers to polyclonal antibodies derived from human plasma, using any of the techniques for making human antibodies as disclosed herein and as known in the art. According to some embodiments, the human polyclonal antibodies disclosed herein are produced by the method disclosed in WO2018/229760.
- the polyclonal antibodies disclosed herein have relatively high specificity to coronavirus and molecules associated therewith.
- the polyclonal antibodies disclosed herein exhibit a binding capacity to coronavirus, or to molecules/antigens/antigen determinants associated therewith, higher than the binding capacity of non-specific (i.e. negative) plasma samples.
- Non-specific, or negative, plasma include plasma derived from one or more human subjects who were not infected by coronavirus and/or do not have antibodies to molecules/antigens/antigen determinants associated with coronavirus and/or plasma derived from one or more human subject prior to the outbreak of COVID-19 pandemics.
- negative plasma samples refers to human plasma samples the binding of which to SARS-CoV-2 was negative (equal or below) relative to a threshold value (calibrator) which corresponds to the binding to SARS-CoV-2 of a plasma pool of donors collected before the COVID-19 pandemic.
- vaccinated human donors refers to subjects that receive any vaccine for coronavirus, including but not limited to, strands of nucleic acids (mRNA) encoding harmless portion of the coronavirus and vaccines that include inactive (dead or weakened) pathogen, or corona virus proteins, all of which induce the immune system of the vaccinated subject to produce antibodies against the virus.
- mRNA nucleic acids
- convalescent vaccinated human donors or “vaccinated convalescent human donors” as used herein are interchangeable and refer to convalescent subjects who were also vaccinated.
- the neutralizing titers of the anti-coronavirus human polyclonal antibodies (Anti-SARS CoV-2) in the final product (the drug product) disclosed herein is at least above 1:1,000. According to some embodiments, the neutralizing titers of the anti-coronavirus human polyclonal antibodies (Anti-SARS CoV-2) disclosed herein is at least above 1:2,000. According to some embodiments, the neutralizing titers of the anti-coronavirus human polyclonal antibodies (Anti-SARS CoV-2) disclosed herein is at least above 1:3,000.
- the neutralizing titers of the anti-coronavirus human polyclonal antibodies (Anti-SARS CoV-2) disclosed herein is at least above 1:4,000. According to some embodiments, the neutralizing titers of the anti-coronavirus human polyclonal antibodies (Anti-SARS CoV-2) disclosed herein is at least above 1:5,000.
- titer refers to the dilution of a solution as determined by titration. With respect to antibodies, this term is determined by finding the highest dilution at which binding of the antibody, or antibodies is still detectable.
- Coronaviruses typically causes the common cold or other mild respiratory viral illnesses, but can cause severe pneumonia and, even death, in some patients. People at highest risk for severe illness from COVID-19 include, but not limited to, those with pre-existing pulmonary disease, imrnune-compromised and the elderly.
- the human anti-coronavirus polyclonal antibodies disclosed herein provide effective therapy to patients afflicted with mild, medium, or severe coronavirus infection, as exemplified below.
- Subjects with mild coronavirus illness may exhibit a variety of signs and symptoms such as, fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, and loss of taste and smell.
- subjects with mild coronavirus do not have shortness of breath, dyspnea on exertion, or abnormal imaging.
- Most of the mildly ill subjects can be managed in an ambulatory setting or at home through telemedicine or telephone visits. Treatment of a mildly ill subject does not usually require imaging or specific laboratory evaluations.
- Elderly subjects and subjects with underlying comorbidities are at higher risk of disease progression and hence may require continuous monitoring by health care providers until clinical recovery is achieved.
- Moderate COVID-19 disease is defined as evidence of lower respiratory disease during clinical assessment or imaging, with Sp0 2 >94% on room air at sea level. Due to the fact that pulmonary diseases can progress rapidly in patients with COVID-19, patients with moderate disease may require close monitoring. In the event that bacterial pneumonia or sepsis is suspected, then antibiotic treatments may be required alone with daily re-evaluations.
- Severe COVID-19 disease is defined in subjects having Sp0 2 ⁇ 94% on room air at sea level, a respiratory rate of >30 breaths/min, Pa0 2 /Fi0 2 ⁇ 300 mmHg, and/or lung infiltrates >50%. These subjects may experience rapid clinical deterioration. Commonly, subjects with severe COVID-19 disease receive oxygen therapy e.g. using a nasal cannula or a high-flow oxygen device. Subjects with severe COVID-19 disease having, or suspected of having, secondary bacterial pneumonia or sepsis also receive antibiotics and are under constant re- evaluation. [0075] According to some embodiments, the coronavirus disease a mild disease.
- coronavirus disease is a mild coronavirus disease.
- a mild disease is a disease associated with at least one mild symptom.
- a mild disease is a disease associated with at least one mild coronavirus symptom.
- a mild disease is a disease with at least one mild symptom associated with coronavirus disease.
- the at least one mild symptom is selected from the group consisting of: fatigue, fever of about 38°C, sore throat, restlessness, pains, including headache and muscle pain, nausea, vomiting, diarrhea, loss of taste and smell, and/or coughing. Each possibility is a separate embodiment of the present invention.
- Mild, or moderate, coronavirus disease and symptoms usually do not require hospitalization. Mild, or moderate, coronavirus disease and symptoms may include one or more of a fever of about 38 °C, coughing and fatigue. Any shortness of breath combined with the aforementioned mild symptoms may indicate the presence of moderate to severe, or severe disease and should be checked. Mild coronavirus infection may include mild form of pneumonia and moderate coronavirus infection may include moderate form of pneumonia. Despite having only mild to moderate symptoms, mild, moderate, or mild to moderate, forms of pneumonia may require hospitalization and antibiotics, along with supplemental oxygen. According to the World Health Organization (WHO) a mild to moderate case of COVID-19 will typically run its course in about two weeks. In addition, 80% of laboratory confirmed cases of COVID-19 cases exhibited mild to moderate symptoms according to data from WHO.
- WHO World Health Organization
- the term "about” refers to a range of values ⁇ 20%, or ⁇ 15% or ⁇ 10%, or ⁇ 5% of a specified value.
- the virus can enter lung cells and start replicating and killing the cells.
- the immune system creates inflammation to fight the virus, this can sometimes result in a more severe form of pneumonia.
- the pharmaceutical composition is for use in the treatment of a disease selected from tracheitis and pneumonia, which relate to, caused by, and/or induced by COVID-19.
- composition is intended to be used herein in its broader sense to include preparations containing the composition used for therapeutic purposes. Accordingly, the pharmaceutical composition contains a therapeutic amount of the active ingredient, namely, the human polyclonal antibodies disclosed herein.
- the pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
- compositions may contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
- an effective dose generally refers to the amount of the composition disclosed herein sufficient to induce immunity, to prevent and/or ameliorate coronavirus infection, or to reduce at least one symptom associated with the coronavirus infection and/or to enhance the efficacy of another therapeutic composition.
- An effective dose may refer to the amount of the composition sufficient to delay or minimize the onset of an infection.
- An effective dose may also refer to the amount of the composition that provides a therapeutic benefit in the treatment or management of infection.
- an effective dose may be the amount with respect to the composition alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of a viral infection.
- An effective dose may also be the amount sufficient to enhance a subject's (in particular, human's) own immune response against a subsequent exposure to virus, specifically, to the coronavirus. The exact effective dose depends on the purpose of the treatment, and is ascertainable by one skilled in the art using known techniques.
- treating refers to taking steps to obtain beneficial or desired therapeutic results.
- beneficial or desired therapeutic results include, but are not limited to, alleviation or amelioration of one or more symptoms associated with an infectious disease, delaying or slowing down the propagation of the disease, amelioration, palliation or stabilization of said disease, among other beneficial results.
- the term “treating” has the meaning of “preventing”.
- the treatment or prevention of a disease is selected from inhibiting viral replication in a subject, inhibiting viral protein synthesis, preventing and/or inhibiting an increase in cell death in a mammal, and preventing and/or inhibiting death.
- prolactic treatment refers to taking steps to prevent the disease, and in particular infectious disease.
- the treatment is passive immunization.
- said treatment comprises one or more of reducing the rate of progression of the disease, inhibiting progression of the disease, preventing the disease and attenuating at least one symptom induced or associated with coronavirus disease.
- said treatment is prevention the occurrence of coronavirus infection.
- said treatment is preventing infection induced by the coronavirus.
- said treatment is prophylactic treatment.
- the subject in need thereof is a healthy subject and the treatment is prophylactic treatment.
- the treatment is a prophylactic immunization.
- the term "healthy subject” as used herein refers to a subject not afflicted with coronavirus infection.
- administering includes any method of delivery of a pharmaceutical composition or agent (i.e., an immunological composition) into a subject's system or to a particular region in, or on, a subject.
- a pharmaceutical composition or agent i.e., an immunological composition
- the immunological compositions and/or antibodies disclosed herein are administered via intramuscular, subcutaneous, intradermal, intranasal, oral, transcutaneous or transmucosal administration.
- administration encompass a singular or multiple instances, respectively, of the delivery of an agent to a subject such that an immunogenically effective singular delivery as well as a priming delivery (first dose of administration) and a subsequent (second, third, etc., doses or administrations) boosting delivery of an agent(s) are encompassed.
- first dose of administration first dose of administration
- second, third, etc., doses or administrations subsequent boosting delivery of an agent(s) are encompassed.
- Example 1 Anti-Coronavirus IgG purified from plasma of convalescent donors
- the anti-coronavirus IgGs were purified using standard Protein G purification process from the plasma of 11 convalescent donors who were coronavirus-free and had a high titer of anti-coronavirus antibodies as determined by a commercial kit (Euroimmun, GmbH).
- the potency of the anti-coronavirus IgG pool obtained from convalescent patients was initially determined by the following proprietary ELISA method using relative units against an in-house calibrator or applying a commercial quantitative kit, as detailed below.
- the in-house calibrator was generated from pool of about 40 plasma samples obtained prior to the emergence of COVID-19 and therefore present the negative response/value.
- 96 well plates were coated with a recombinant structural protein of SARS-CoV-2, namely, the spike protein receptor binding domain (RBD; Sino Biological).
- the plates were then incubated with the human polyclonal anti-SARS-CoV-2 IgG samples obtained from individual plasma donations which underwent various purification stages of the manufacturing process: (1) manufacturing plasma pool, (2) post DEAE column, (3) post complete cleaning based on the protocol disclosed in WO2018/229760 (also termed Drug Substance; DS), and (4) the latter (clean) diluted as required for clinical applications (also termed Drug Product; DP).
- Bound antibodies were detected with anti-human IgG conjugated to horse radish peroxidase (HRP) and the resulting absorbance was measured at 450 nm after adding the HRP substrate. The extinction value of the calibrator was used as the cutoff, and is also termed herein negative value.
- Figure 1 A exhibits Fold positive results of four sample types: manufacturing plasma pool (sample 62201)- which is the starting material post filtration, in process (partially purified) sample after the first column, namely, the DEAE column (sample 63301), Drug Substance (DS) and drug product (DP).
- the commercial quantitative kit QuantiVac manufactured by Euroimmun Germany was used to quantify the amount of anti SARS CoV-2 IgG in international binding antibody unit (BAU) calibrated against WHO standard 20/136.
- This ELISA plat is coated with SI protein and the detection is performed with anti-human IgG conjugated to horse radish peroxidase (HRP) and the resulting absorbance was measured at 450 nm after adding the HRP substrate.
- the concentrations of anti SARS CoV-2 IgG, using the commercial kit were evaluated for four representative batches, expressed as international binding antibody unit per mL (BAU/mL), where for each batch the concentration is provided for the crude plasma pool, the drug substance and the drug product (Fig. IB and Table 1).
- the association of Spike with IgGs was monitored by injecting different concentrations of the IgGs Drug Substance (ranging from 200 nM to 3,200 nM) for 2-4 min at a flow rate of 30 pL/min (Table 2 and Fig. 2).
- the dissociation of the IgGs from Spike was investigated by stopping their injection. NaOH (10 mM) was used to regenerate the chip.
- Table 2 Association, dissociation and affinity constant determined for the drug substance ka-associate constant; kd dissociation constant; KD - affinity constant
- PRNT is a serological test that utilizes the ability of a specific antibody to neutralize a virus and prevent the virus from forming plaques in a cell monolayer.
- the assay involves mixing a constant amount of virus, determined by virus titration performed on the same cell type, prior to each neutralization assay, with dilutions of the serum specimen being tested, followed by plating the mixture onto cells of an appropriate cell line for the individual virus.
- the neutralization dose 50 (ND50) which is the dose that neutralize 50% of the virus activity, is determined by the number of plaques formed after a few days.
- the PRNT test for SARS-CoV-2 involved the following steps: a plasma sample containing antibody against SARS-CoV-2 was diluted in serial dilutions of 1/10, 1/20, 1/40, 1/80, 1/160, 1/320 in duplicate (or any further dilution depending on the neutralization capability); samples were incubated with SARS-CoV-2 virus for 1 hour (the exact concentration was determined prior to the assay), then confluent Vero/E6 cells were exposed to/incubated with the mixture of virus + tested sample and overlay media, for 5 days. At the end of the incubation, cells were fixed and stained to expose plaques. The positive control was a known neutralizing serum, while the negative control was only the virus. The dilution of the sample which reduces the number of plaques by 50% compared to the control, neutralization dose 50 (ND50), was calculated and expressed as titer value.
- ND50 neutralization dose 50
- Plasma manufacturing pool sample of R&D batch and of clinical batch starting material; white columns
- results show the enrichment of the anti-SARS-CoV-2 neutralizing antibodies over the process, starting from ND50s of 542 and 278 in the plasma manufacturing pool samples and ending with ND50s of 3186 and 2989 in the drug products (R&D batch and clinical batch, respectively).
- the results further indicate that the drug product is about 10 times (an order of magnitude) more potent than the starting material (plasma pool).
- the anti SARS CoV-2 IgG disclosed herein are effective against wild type SARS CoV-2 and variants thereof.
- Example 4 Product characterization
- the different immunoglobulin isotypes were tested in the final product using a method similar to the semi quantitation of anti SARS CoV-2 IgG presented above, where the detection antibody was anti human IgG, IgA, and IgM.
- the results, presented in Fig. 6, indicate that the predominant isotype in the drug product is IgG with negligible amounts of IgM and IgA.
- the distribution of the various IgG subclasses in the final product was tested.
- the results, presented in Fig. 7, indicate that the drug product includes primarily the isotypes IgGl, IgG2, and IgG3, wherein the drug product is practically lacking the IgG4 isotype (exhibits very low levels of this isotype).
- the Anti-SARS-CoV-2 IgG product has comparable (relative to plasma) distribution of the IgG, as follows: IgGl: 68%, IgG2: 25%, IgG3: 6% and IgG4: 0.2%.
- the level of IgG4 is consistently lower than in the plasma in comparison to other IgG subclasses as this IgG subclass is significantly reduced during the manufacturing process.
- the purification process utilized in the production of the Anti-SARS-CoV-2 IgG product disclosed herein reduces the plasma protein impurities (e.g. transferrin, ceruloplasmin, IgA) to very low levels, resulting in a highly purified product with a very low level of process related impurities.
- Example 5 Anti-Coronavirus hyper-immune IgG and uses thereof for studies in hamster models
- the aims of these studies were to prepare human plasma-derived Anti- SARS-CoV- 2 IgG for systemic injection (intraperitoneal (IP)) to hamsters and evaluate the efficacy of the anti- coronavirus antibodies in terms of protection, and moreover prevention, against coronavirus infection or attenuation of infection and observed clinical signs. Furthermore, the studies' objective was to provide a medical countermeasure against infection and disease caused by the SARS-CoV-2.
- Plasma units from COVID-19 convalescent donors were pooled and IgGs were purified using the aforementioned proprietary manufacturing facility GMP process, to obtain a purified preparation of anti-coronavirus IgGs.
- the plasma pool titer was determined using ELISA method and a neutralization cellular assay (Plaque Reduction Neutralization Test, PRNT). Plasma pool was aliquoted and kept frozen for use and establishment of the therapeutic dose.
- the titer of the drug product (DP), containing the purified IgGs was determined using PRNT.
- the resulting DP also termed herein Anti- SARS-CoV-2 IgG or hyperimmune IgG, was aliquoted and kept frozen for use.
- hyper-immune IgG and “hyperimmune IgG” are interchangeable and generally refer to immunoglobulins prepared in a similar way as for normal human immunoglobulin, except that the donors have high titers of antibody against a specific organism or antigen in their plasma.
- Viral loads in nasal washes, nasal turbinate tissue, trachea and lungs were assessed using a qRT-PCR method for viral RNA titer and tissue culture method for infectious virus titer. Histopathologic alterations of trachea and lungs were evaluated. Immunohistochemical studies for SARS-CoV- 2 virus were performed on the lungs. Human IgG in the hamster plasma was determined using a commercial ELISA kit.
- the anti SARS-CoV-2-IgG product disclosed herein prevent damages caused by SARS CoV-2 virus and hence can be used as prophylactic treatment.
- the ferrets are challenged intranasally (0.25 ml/nare), with a viral dose of: lxlO 6 TCID50 SARS-CoV-2.
- Nasal wash samples are taken for viral RNA detection and live virus determination.
- Blood samples are taken for ELISA analysis. Weight clinical signs and temperature of the animals are measured during the study.
- Necropsy and tissue collections (lung, nasal turbinates, and trachea) are conducted on day 7 post infection for histology and pathology assessments.
- Example 7 Clinical study: Anti-SARS-CoV-2 for treatment of COVID-19 patients hospitalized with pneumonia
- a phase 1/2 open label, single arm study to evaluate the safety, pharmacokinetics and pharmacodynamics of single dose Anti-SARS-CoV-2 was conducted with COVID-19 hospitalized patients with pneumonia.
- This phase 1/2 open label single arm study was designed to assess the safety pharmacokinetics and pharmacodynamics of the anti-coronavirus human polyclonal antibodies disclosed herein (also termed "Anti-SARS-CoV-2") in non-ventilated patients with pneumonia within 10 days of symptom onset. This population is also referred to as COVID-19 patients with moderate to severe disease.
- a total of 12 eligible patients were enrolled and received the polyclonal antibodies disclosed herein, namely, Anti-SARS-CoV-2 at a single dose of 4 g IgG, via intravenous infusion.
- Dosing should be within 10 days of symptom start.
- ICF Informed Consent Form
- Duration of the study was 84 days. Treatment was initiated on day 1, and each patient was followed up until day 84.
- an adverse event is any untoward medical occurrence in a patient or clinical study patient, temporally associated with the use of investigational product, whether or not considered related to the investigational product.
- a serious AE is commonly defined as any untoward medical occurrence that either: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity and/or is a congenital anomaly/birth defect.
- Table 9 summarizes the hospital duration, ICU and mechanical ventilation. Table 9: Covid-19 Related Hospitalization Duration
- Each patient was given a score from 1-6 based on the clinical status at the time of assessment, as shown in Table 10. The assessment was done at screening (eligible patients have a score of 3-5), and at days 1, 7, 14, 21, 28, 56 and 84. The 6-Ordinate scores are described in Table 10.
- Table 10 6-Ordinate Clinical Status score scale
- the neutrophil to lymphocyte ratio is a risk marker for severe COVID-19 disease, with a value of above 3.13 at age >50 marking a 50% risk of severe disease.
- 9/12 patients displayed a ratio of 3.13 and above, indicating that about half of the patients were at risk of severe disease.
- the neutrophil to lymphocyte ratios are of the 12 patients are provided in Table 11.
- Table 11 Ratio Neutrophils/Lymphocytes
- the results of the clinical study indicate that the Anti-SARS-CoV-2 human polyclonal antibodies disclosed herein has a good safety profile with no evidence of infusion associated adverse events or anaphylaxis. Specifically, adverse reactions were not documented, and serious adverse event were minor compared to the entire group of patients (16.7%). Moreover, the clinical condition of 11 of the 12 patients (91.7%) improved after a single administration of the antibodies and were discharged from hospital after a median duration of 5 days from antibodies administration (which is equivalent to 6 days from hospitalization).
- terms such as “processing”, “computing”, “calculating”, “determining”, “estimating”, “assessing”, “gauging” or the like may refer to the action and/or processes of a computer or computing system, or similar electronic computing device, that manipulate and/or transform data, represented as physical (e.g. electronic) quantities within the computing system’s registers and/or memories, into other data similarly represented as physical quantities within the computing system’s memories, registers or other such information storage, transmission or display devices.
Abstract
Provided herein are compositions comprising human polyclonal antibodies and methods of using same for treating or preventing coronavirus infections and diseases, disorders and symptoms associated with coronavirus infection.
Description
COMPOSITIONS AND METHODS FOR TREATING INFECTIOUS DISEASE
CAUSED BY CORONA VIRUS
FIELD OF THE INVENTION
[0001] Provided herein are compositions comprising human polyclonal antibodies and methods of using same for treating or preventing coronavirus infections and diseases, disorders and symptoms associated with coronavirus infection.
BACKGROUND
[0002] Coronaviruses are enveloped, positive-sense single-stranded RNA viruses. They have the largest genomes (26-32 kb) among known RNA viruses, and are phylogenetically divided into four genera (alpha, beta, gamma, delta), with beta-coronaviruses further subdivided into four lineages (A, B, C, D). Coronaviruses infect a wide range of avian and mammalian species, including humans. Of the six known human coronaviruses, four (HCoV- OC43, HCoV-229E, HCoV-HKUl, and HCoV-NL63) circulate annually in humans and generally cause mild respiratory diseases, although severity can be greater in infants, elderly, and the immunocompromised. In contrast, the Middle East respiratory syndrome coronavirus (MERS-CoV) and the severe acute respiratory syndrome coronavirus (SARS-CoV), belonging to betacoronavirus lineages C and B, respectively, are highly pathogenic. Both viruses emerged into the human population from animal reservoirs within the last 15 years and caused outbreaks with high case-fatality rates.
[0003] The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus induced disease 19 (CQVID-19) that emerged in China in late 2019 and became the cause of a pandemic. As of October 2020, over 48M cases have been reported worldwide, of whom an estimated 2% succumbed to the infection. SARS-CoV-2 belongs to the Sarbecovirus subgenus (genus Betacoronavirus, family Coronaviridae), as does the SARS-CoV that emerged in 2002 and caused -8,000 infections with a lethality of 10%. Both viruses can cause a life-threatening respiratory illness in humans. Remdesivir (Veklury®) was approved in the US for hospitalized patients with COVID-19, but has only shown a modest benefit. Dexamethasone is also recommended by the NTH for patients who are ventilated or in need of supplemental oxygen.
[0004] The high infection rate, vaguely defined epidemiology, and absence of prophylactic or therapeutic measures against coronaviruses have created an urgent need for effective preventive and therapeutic agents.
SUMMARY
[0005] There are provided pharmaceutical compositions comprising anti-coronavirus human polyclonal antibodies and use thereof for treating and preventing COVID-19 and symptoms associated therewith.
[0006] The term "COVID-19" as used herein is interchangeable with the terms "coronavirus disease", "COVID-19 disease", and further refers to diseases, disorders, and symptoms associated with the COVID-19 infection.
[0007] Advantageously, treating or preventing coronavirus infection by using the human polyclonal antibodies disclosed herein is superior to use of a single monoclonal antibody, due to the broader spectrum of epitopes that are targeted by polyclonal antibodies purified from plasma pools of heterogeneous human donors.
[0008] Furthermore, treating or preventing coronavirus infection by using the human polyclonal antibodies disclosed herein is advantageous over the use of whole plasma derived from convalescent donors from a safety perspective, as the purification methods used for obtaining the human polyclonal antibodies minimizes known and potentially severe side effects, such as, transfusion reactions, allergic reactions to plasma contents, ABO incompatibility, and potential exposure to HBV, HCV and HIV among others viruses.
[0009] Preliminary analysis of the neutralizing titers of the anti-coronavirus human polyclonal antibodies (Anti-SARS CoV-2) disclosed herein indicate that the effective dose of said anti-coronavirus human polyclonal antibodies requires relatively low volume, which provides a significant advantage compared to convalescent plasma (CP). An effective dose of CP requires about 200-400 ml, compared to the volume of Anti-SARS CoV-2 which is less than 100 ml. Administration of high volumes, over 100 ml, introduces high clinical risks, especially to challenged patients, such as, patients infected with coronavirus, elderly patients, and the like. This is because, administration of large volumes may overload the circulatory system due to excess fluid volume. The latter may be life-threatening to patients suffering from heart failure, which is one of the common disorders associated with coronavirus infection. It is
well known that the increase in fluid volume increases the burden on the weakened heart, further exacerbating the problem. Moreover, delivery of large volumes must be carried out by intravenous infusion, while delivery of a small volume, below 100 ml, can be performed via more comfortable routes of administration, including, but not limited to, intravenous infusion, subcutaneously, intraperitoneally (i.p.) and i.v. injection, which are fast, cost effective and altogether enable more convenient routes of administration, which altogether provide improved compliance. Compliance is important in ensuring an improved health outcome for the patients, especially those suffering from a chronic condition and/or requiring prolonged medical attention.
[0010] Surprisingly, as shown hereinbelow, prophylactic treatment with the anti-SARS CoV-2 IgG disclosed herein prevents the significant loss of body weight induced by SARS CoV-2. Furthermore, the healing effect of the anti-SARS CoV-2 antibodies disclosed herein, is dose dependent, enabling to tailor a dose per severity of the SARS CoV-2 infection, symptoms and/or side-effects.
[0011] Unexpectedly, the anti-SARS CoV-2 antibodies disclosed herein provides an effective treatment not only against the SARS CoV-2 wild type, but also against variants thereof, including, but not limited to, the South African and the British variants.
[0012] According to some embodiments, there is provided a method for treating COVID- 19 disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising anti-coronavirus human polyclonal antibodies.
[0013] According to some embodiments, said treating COVID-19 comprises treating disease or disorders associated with COVID-19. According to some embodiments, the disease or disorders associated with COVID-19 comprise influenza, tracheitis and pneumonia.
[0014] According to some embodiments, the anti-coronavirus human polyclonal antibodies comprise anti-coronavirus human polyclonal IgG.
[0015] According to some embodiments, the anti-coronavirus human polyclonal IgG comprise anti-coronavirus human polyclonal IgGl, anti-coronavirus human polyclonal IgG2 and anti-coronavirus human polyclonal IgG3.
[0016] According to some embodiments, the anti-coronavirus human polyclonal IgG is devoid of anti-coronavirus human polyclonal IgG4. According to some embodiments, the anti- coronavirus human polyclonal IgG has low amounts of anti-coronavirus human polyclonal IgG4, relative to the amounts of anti-coronavirus human polyclonal IgGl-3.
[0017] According to some embodiments, the anti-coronavirus human polyclonal antibodies comprise trace amounts of IgM and IgA. According to some embodiments, the anti-coronavirus human polyclonal antibodies comprise negligible amounts of IgM and IgA. According to some embodiments, the anti-coronavirus human polyclonal antibodies comprise low amounts of IgM and IgA relative to the amounts of IgG.
[0018] According to some embodiments, the anti-coronavirus human polyclonal antibodies are derived from the plasma of convalescent human donors. According to some embodiments, the anti-coronavirus human polyclonal antibodies are derived from the plasma of convalescent vaccinated human donors. According to some embodiments, the anti-coronavirus human polyclonal antibodies are derived from the plasma of vaccinated human donors.
[0019] According to some embodiments, the COVID-19 disease is induced by SARS- CoV-2 and variants thereof. According to some embodiments, the COVID-19 disease is induced by SARS-CoV-2 (wild type). According to some embodiments, the COVID-19 disease is induced by variants of SARS-CoV-2.
[0020] According to some embodiments, the COVID-19 disease is mild. According to some embodiments, the COVID-19 disease is moderate. According to some embodiments, the COVID-19 disease is severe.
[0021] According to some embodiments, the COVID-19 disease comprises pneumonia. According to some embodiments, the COVID-19 disease comprises tracheitis. According to some embodiments, the COVID-19 disease comprises influenza.
[0022] According to some embodiments, the pharmaceutical composition is in a liquid form.
[0023] According to some embodiments, the pharmaceutical composition is for intravenous use. According to some embodiments, the pharmaceutical composition is for
intravenous bolus administration. According to some embodiments, the pharmaceutical composition is for intravenous infusion.
[0024] According to some embodiments, the anti-coronavirus human polyclonal antibodies have a titer higher than 1 :500. According to some embodiments, the anti-coronavirus human polyclonal antibodies have a titer higher than 1:1,000. According to some embodiments, the anti-coronavirus human polyclonal antibodies have a titer higher than 1:2,000.
[0025] According to some embodiments, the anti-coronavirus human polyclonal antibodies have a binding capacity to coronavirus, or to antigen associated therewith, which is at least 6- fold higher than the binding capacity of negative plasma samples derived from one or more human donors who were not infected by coronavirus and/or do not have antibodies to determinants associated with coronavirus.
[0026] According to some embodiments, said administering comprises at least one administration. According to some embodiments, said administering comprises a plurality of administration.
[0027] According to some embodiments, said treatment is prophylactic treatment.
[0028] According to some embodiments, said subject in need thereof is a healthy subject and the treatment is prophylactic. According to some embodiments, the subject in need thereof is a subject afflicted with COVID-19, having mild symptoms, and the treatment is prophylactic, aimed to prevent hospitalization, and/or to prevent exacerbation of COVID-19.
[0029] According to some embodiments, there is provided a pharmaceutical composition comprising anti-coronavirus human polyclonal antibodies method for the treatment of COVID- 19 disease.
[0030] According to some embodiments, the pharmaceutical composition is in a liquid form.
[0031] According to some embodiments, the pharmaceutical composition is for intravenous use.
[0032] According to some embodiments, said treatment is prophylactic treatment.
[0033] Other objects, features and advantages of the present invention will become clear from the following description, examples and drawings.
[0034] Certain embodiments of the present disclosure may include some, all, or none of the above advantages. One or more other technical advantages may be readily apparent to those skilled in the art from the figures, descriptions, and claims included herein. Moreover, while specific advantages have been enumerated above, various embodiments may include all, some, or none of the enumerated advantages.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] Some embodiments of the disclosure are described herein with reference to the accompanying figures. The description, together with the figures, makes apparent to a person having ordinary skill in the art how some embodiments may be practiced. The figures are for the purpose of illustrative description and no attempt is made to show structural details of an embodiment in more detail than is necessary for a fundamental understanding of the disclosure. For the sake of clarity, some objects depicted in the figures are not to scale.
In the Figures:
[0036] Fig. 1A demonstrates preliminary results of the IgG titer from four main manufacturing process steps: sample (62201) is filtrated plasma pool taken from convalescent donors, sample (63301) is the diluted sample post DEAE column with IgG purification of >95%, DS is the concentrated Drug Substance and DP is the final drug product. Anti SARS- CoV-2 IgG content is expressed as fold positive binding assay results.
[0037] Fig. IB demonstrates the concentration of anti SARS CoV-2 IgG from four representative batches denoted 111120DV, 121120DV, 131220AV and 010121AV. For each batch, the first sample (left column, light grey) is the titer of filtrated plasma pool taken from convalescent donors, the second sample (middle column, black) is the titer concentrated Drug Substance (DS) and the third sample (right column, dark grey) is the final drug product (DP).
[0038] Fig. 2 shows the Surface Plasmon Resonance Measurements of the purified IgG from convalescent donors' plasma.
[0039] Fig. 3 represents the correlation between the fold positive (FP) results obtained by the commercial kit of Euroimmun and the results obtained by the proprietary screening assay, for convalescent plasma samples.
[0040] Fig. 4A represents PRNT neutralization results.
[0041] Fig. 4B represents the high correlation between anti SARS COV-2 IgG concentration determined by ELISA and the neutralization activity.
[0042] Fig. 4C represents the anti SARS CoV-2 IgG neutralization activity against two SARS COV-2 variants: the South African variant (SA) and the British variant (UK).
[0043] Fig. 5 represents the end point titer of the drug product.
[0044] Fig. 6 represents the various immunoglobulin isotypes in the drug product.
[0045] Fig. 7 represents the various IgG subclasses in the drug product.
[0046] Fig. 8 represents body changes in body weight over time in Syrian golden hamsters challenged with SARS Cov-2, and either not treated (vehicle) or treated with the IgG disclosed herein, as follows: 330 mg/kg prophylactic treatment (circle solid line, one day prior to challenge with SARS Cov-2); prophylactic vehicle (square); 330 mg/kg treatment (upward triangle); vehicle (downward triangle); 55 mg/kg treatment (diamond); and 330 mg/kg treatment (circle, broken line).
DETAILED DESCRIPTION
[0047] The principles, uses and implementations of the teachings herein may be better understood with reference to the accompanying description and figures. Upon perusal of the description and figures present herein, one skilled in the art will be able to implement the teachings herein without undue effort or experimentation.
[0048] In the description and claims of the application, the words “include” and “have”, and forms thereof, are not limited to members in a list with which the words may be associated.
[0049] Provided herein is treatment for coronavirus, such as, COVID-19, also termed hereinafter, SARS-CoV-2 or wild-type SARS-CoV-2 and variants thereof, such as the British variant and the South African variant. The Anti-SARS-CoV-2 is a Human Severe Acute
Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) immune gamma globulin preparation that is manufactured from convalescent plasma of COVID- 19 recovered patients, using suitable purification methods, as disclosed herein. Purified immunoglobulins from convalescent plasma are expected to be superior to plasma as they are pooled from a large antibody repertoire, eliminate the need for donor and recipient matching, reduce the risk for blood-borne infectious agents, have a lower volume, and do not require freezing and thawing.
[0050] The term coronavirus as used herein, includes, but is not limited to, anyone or more of SARS-CoV-2, MERS-CoV, SARS-CoV, NL63-CoV, 229E-CoV, OC43-CoV, HKUl-CoV, WIVl-CoV, MHV, HKU9-CoV, PEDV-CoV, and SDCV. Furthermore, this term includes variants of SARS-CoV-2, such as, the British/UK variant (B.1.1.7) also known as the alpha variant and the South African variant, also known as beta variant (B.1.351). It is note that viruses constantly change through mutation, where a variant has one or more mutations that differentiate it from other variants in circulation. The B.1.1.7 (Alpha), B.1.351 (Beta), P.l (Gamma), B.1.427 (Epsilon), B.1.429 (Epsilon), and B.1.617.2 (Delta) variants circulate in the United States and are classified as variants of concern. Accordingly, it has been suggested that specific monoclonal antibody treatments may be less effective for treating cases of COVID- 19 caused by variants.
[0051] Passive immunization therapy is intended to provide immediate immunity to susceptible individuals, and has been proved to be beneficial for the treatment of various diseases, including infections from SARS and MERS respiratory viruses. Passive immunization therapy was first used in the 1890s and helped reduce the severity of a number of infectious disease outbreaks prior to the development of antimicrobial therapy in the 1940s.
[0052] In the early 20th century, the use of plasma from recovered individuals (convalescent plasma) was used as a therapy during outbreaks of measles, mumps, and influenza. It was used during the H1N1 influenza pandemic in 2009 and again in 2013 during the Ebola outbreak in West Africa and SARS-CoV-1 infection. A small non-randomized study in Sierra Leone revealed a significant increase in survival for patients treated with convalescent whole blood relative to those who received standard treatment.
[0053] Experience from prior outbreaks with other coronaviruses, such as SARS-CoV-1 shows that convalescent plasma contains neutralizing antibodies to the relevant virus. In the case of SARS-CoV-2, the anticipated mechanism of action by which passive immunization
therapy mediates protection is viral neutralization. However, other mechanisms may be possible, such as antibody dependent cellular cytotoxicity and/or phagocytosis.
[0054] In previous SARS and MERS outbreaks, the high mortality and absence of effective therapies led to the use of convalescent plasma in human studies. The largest study involved the treatment of 80 patients in Hong Kong with SARS. Patients treated before day 14 had improved prognosis defined as hospital discharge before day 22, consistent with the notion that earlier treatment administration is more likely to be effective. In addition, patients who were PCR positive and seronegative for coronavirus at the time of treatment had improved prognosis. There is also some anecdotal information on the use of convalescent plasma in seriously ill individuals. Three patients with SARS in Taiwan were treated with 500 ml of convalescent plasma, resulting in a reduction in plasma virus titer.
[0055] A report from South Korea describes three patients with MERS who were treated with convalescent plasma, but only two of the recipients demonstrated neutralizing antibodies in their plasma. The latter study highlights a challenge in using convalescent plasma, namely, that some individuals who recover from a viral disease may not have high titers of neutralizing antibodies. Consistent with this point, an analysis of 99 samples of convalescent sera from patients with MERS showed that 87 of them had neutralizing antibodies with a geometric mean titer of 1:61. This suggests that antibody levels decline with time and/or that few patients demonstrate high titer responses. Furthermore, it indicates that antibodies derived from convalescent plasma are not necessarily effective therapeutically.
[0056] For passive immunization therapy to be effective, a sufficient amount of neutralizing antibodies must be administered. When given to a susceptible person, the antibodies circulate in the blood, reach the tissues and provide protection against infection. Depending on the antibody amount and composition, the protection conferred by this treatment can last from weeks to months.
[0057] A general principle of passive immunization therapy is that it is most effective when administered shortly after the onset of symptoms. The reason for the temporal variation in efficacy is not well understood but could reflect the observation that passive immunization works by neutralizing the initial inoculum, which is likely to be much smaller than the viral load seen in established disease following viral spread. Another explanation is that antibodies work by modifying the modest inflammatory response observed during the initial phase of the
disease, which maybe asymptomatic. As an example, passive immunization therapy for pneumococcal pneumonia was found to be most effective when administered shortly after the onset of symptoms and there was no benefit if antibody administration was delayed past the third day of disease.
[0058] Convalescent plasma (CP) therapy has several limitations. For example, CP infusions can transmit blood-borne infections, and induce febrile and allergic transfusion reactions, anaphylaxis in IgA-deficient recipients, transfusion-associated circulatory overload, and transfusion-related acute lung injury. In addition, there is significant variability between plasma units (e.g., variation of antibody specificity, affinity, and concentration). A gamma globulin therapy using the purified anti-coronavirus human polyclonal antibodies disclosed herein beneficially circumvents the limitations of CP. The disclosed anti-coronavirus human polyclonal antibodies are produced from multiple donors, which are pooled. The gamma globulins are then highly purified, and aliquoted into injectable doses, which are standardized for antibody characteristics. Thus, the resulting gamma globulin composition has batch-to- batch consistency, provides higher concentrations of antibodies that can be readily given as a small- volume, preferably intravenously, and has less risk of causing serious transfusion-related adverse events (e.g., blood borne pathogen transmission, transfusion reactions). Moreover, production of the highly purified immunoglobulins is scalable and the resulting products can be stored refrigerated for prolonged durations without the need to freeze the sample, as is the case with plasma samples. This provides a practical approach for disseminating this treatment widely.
[0059] Thus, according to some embodiments, there is provided a pharmaceutical composition comprising a therapeutically effective amount of purified human polyclonal antibodies against coronavirus for use in the treatment or prophylaxis of infection in a mammal arising from coronavirus. As shown herein, the purified anti-coronavirus human polyclonal antibodies disclosed herein demonstrate safety and efficacy for the treatment of patients with COVID-19 infection induced by SARS-CoV-2 and variants thereof.
[0060] As used herein, an "antibody" refers to a polypeptide substantially encoded by an immunoglobulin gene(s), which recognizes an epitope (antigen), and has the ability to bind thereto. The recognized immunoglobulin encoding genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. An exemplary immunoglobulin (antibody) structural unit is composed
of two pairs of polypeptide chains, each pair having one "light" (about 25 kD) and one "heavy" chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chains, respectively. In a particular exemplary embodiment, the immunoglobulin will consist of an immunoglobulin preparation isolated from pooled plasma (preferably human plasma) comprising IgG immunoglobulins. The light chains are commonly classified as kappa or lambda and the heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD, and IgE, respectively.
[0061] Immunoglobulins can be produced from the plasma of unselected donors, while the anti-coronavirus immunoglobulins disclosed herein were produced from the plasma of donors with high antibody titers against the receptor binding domain (RBD) of the S 1 protein of the SARS CoV-, in a process that included meticulous screening steps of the plasma, as detailed below. According to some embodiments, the anti-coronavirus immunoglobulins are derived from convalescent donors. According to some embodiments, the convalescent donors are donors identified during the convalescent period after infection. According to some embodiments, the anti-coronavirus immunoglobulins are derived from donors specifically vaccinated.
[0062] The term “polyclonal antibodies” are used herein denotes a mixture of different antibody molecules that react with more than one immunogenic determinant of an antigen. In the present context, the term “polyclonal antibodies” encompasses polyclonal antibodies preparation isolated or purified from human blood, serum or plasma, namely, human polyclonal antibodies.
[0063] The term "human polyclonal antibodies" as used herein refers to polyclonal antibodies derived from human plasma, using any of the techniques for making human antibodies as disclosed herein and as known in the art. According to some embodiments, the human polyclonal antibodies disclosed herein are produced by the method disclosed in WO2018/229760.
[0064] According to some embodiments, the polyclonal antibodies disclosed herein have relatively high specificity to coronavirus and molecules associated therewith. The polyclonal antibodies disclosed herein exhibit a binding capacity to coronavirus, or to
molecules/antigens/antigen determinants associated therewith, higher than the binding capacity of non-specific (i.e. negative) plasma samples. Non-specific, or negative, plasma include plasma derived from one or more human subjects who were not infected by coronavirus and/or do not have antibodies to molecules/antigens/antigen determinants associated with coronavirus and/or plasma derived from one or more human subject prior to the outbreak of COVID-19 pandemics. Accordingly, the term "negative plasma samples" as used herein refers to human plasma samples the binding of which to SARS-CoV-2 was negative (equal or below) relative to a threshold value (calibrator) which corresponds to the binding to SARS-CoV-2 of a plasma pool of donors collected before the COVID-19 pandemic.
[0065] The term "vaccinated human donors" as used herein refers to subjects that receive any vaccine for coronavirus, including but not limited to, strands of nucleic acids (mRNA) encoding harmless portion of the coronavirus and vaccines that include inactive (dead or weakened) pathogen, or corona virus proteins, all of which induce the immune system of the vaccinated subject to produce antibodies against the virus.
[0066] The terms "convalescent vaccinated human donors" or "vaccinated convalescent human donors" as used herein are interchangeable and refer to convalescent subjects who were also vaccinated.
[0067] According to some embodiments, the neutralizing titers of the anti-coronavirus human polyclonal antibodies (Anti-SARS CoV-2) in the final product (the drug product) disclosed herein is at least above 1:1,000. According to some embodiments, the neutralizing titers of the anti-coronavirus human polyclonal antibodies (Anti-SARS CoV-2) disclosed herein is at least above 1:2,000. According to some embodiments, the neutralizing titers of the anti-coronavirus human polyclonal antibodies (Anti-SARS CoV-2) disclosed herein is at least above 1:3,000. According to some embodiments, the neutralizing titers of the anti-coronavirus human polyclonal antibodies (Anti-SARS CoV-2) disclosed herein is at least above 1:4,000. According to some embodiments, the neutralizing titers of the anti-coronavirus human polyclonal antibodies (Anti-SARS CoV-2) disclosed herein is at least above 1:5,000.
[0068] The term "titer" as used herein refers to the dilution of a solution as determined by titration. With respect to antibodies, this term is determined by finding the highest dilution at which binding of the antibody, or antibodies is still detectable.
[0069] Coronaviruses typically causes the common cold or other mild respiratory viral illnesses, but can cause severe pneumonia and, even death, in some patients. People at highest risk for severe illness from COVID-19 include, but not limited to, those with pre-existing pulmonary disease, imrnune-compromised and the elderly.
[0070] According to some embodiments, the subject in need thereof is a subject afflicted with coronavirus disease (e.g. COVID-19 disease). The term "coronavirus disease" as used herein is exchangeable with "coronavirus infection".
[0071] The human anti-coronavirus polyclonal antibodies disclosed herein provide effective therapy to patients afflicted with mild, medium, or severe coronavirus infection, as exemplified below.
[0072] Subjects with mild coronavirus illness (disease) may exhibit a variety of signs and symptoms such as, fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, and loss of taste and smell. Typically, subjects with mild coronavirus do not have shortness of breath, dyspnea on exertion, or abnormal imaging. Most of the mildly ill subjects can be managed in an ambulatory setting or at home through telemedicine or telephone visits. Treatment of a mildly ill subject does not usually require imaging or specific laboratory evaluations. Elderly subjects and subjects with underlying comorbidities are at higher risk of disease progression and hence may require continuous monitoring by health care providers until clinical recovery is achieved.
[0073] Moderate COVID-19 disease is defined as evidence of lower respiratory disease during clinical assessment or imaging, with Sp02 >94% on room air at sea level. Due to the fact that pulmonary diseases can progress rapidly in patients with COVID-19, patients with moderate disease may require close monitoring. In the event that bacterial pneumonia or sepsis is suspected, then antibiotic treatments may be required alone with daily re-evaluations.
[0074] Severe COVID-19 disease is defined in subjects having Sp02 <94% on room air at sea level, a respiratory rate of >30 breaths/min, Pa02/Fi02 <300 mmHg, and/or lung infiltrates >50%. These subjects may experience rapid clinical deterioration. Commonly, subjects with severe COVID-19 disease receive oxygen therapy e.g. using a nasal cannula or a high-flow oxygen device. Subjects with severe COVID-19 disease having, or suspected of having, secondary bacterial pneumonia or sepsis also receive antibiotics and are under constant re- evaluation.
[0075] According to some embodiments, the coronavirus disease a mild disease. According to some embodiments, coronavirus disease is a mild coronavirus disease. According to some embodiments, a mild disease is a disease associated with at least one mild symptom. According to some embodiments, a mild disease is a disease associated with at least one mild coronavirus symptom. According to some embodiments, a mild disease is a disease with at least one mild symptom associated with coronavirus disease. According to some embodiments, the at least one mild symptom is selected from the group consisting of: fatigue, fever of about 38°C, sore throat, restlessness, pains, including headache and muscle pain, nausea, vomiting, diarrhea, loss of taste and smell, and/or coughing. Each possibility is a separate embodiment of the present invention.
[0076] According to some embodiments, the coronavirus disease a moderate disease. According to some embodiments, coronavirus disease is a moderate coronavirus disease. According to some embodiments, a moderate disease is a disease associated with at least one moderate symptom. According to some embodiments, a moderate disease is a disease associated with at least one moderate coronavirus symptom. According to some embodiments, a moderate disease is a disease with at least one moderate symptom associated with coronavirus disease. According to some embodiments, the at least one moderate symptom is selected from the group consisting of: SpCh >94% on room air at sea level and/or moderate pneumonia. Each possibility is a separate embodiment of the present invention.
[0077] Mild, or moderate, coronavirus disease and symptoms usually do not require hospitalization. Mild, or moderate, coronavirus disease and symptoms may include one or more of a fever of about 38 °C, coughing and fatigue. Any shortness of breath combined with the aforementioned mild symptoms may indicate the presence of moderate to severe, or severe disease and should be checked. Mild coronavirus infection may include mild form of pneumonia and moderate coronavirus infection may include moderate form of pneumonia. Despite having only mild to moderate symptoms, mild, moderate, or mild to moderate, forms of pneumonia may require hospitalization and antibiotics, along with supplemental oxygen. According to the World Health Organization (WHO) a mild to moderate case of COVID-19 will typically run its course in about two weeks. In addition, 80% of laboratory confirmed cases of COVID-19 cases exhibited mild to moderate symptoms according to data from WHO.
[0078] The vast majority of patients have mild or moderate symptoms can heal by resting, drinking plenty of water, and staying home. Some patients, typically those who are elderly or
with underlying health issues, may develop moderate symptoms that could require supportive care, such as i.v. infusion of fluids for dehydration.
[0079] In about one in five patients with mild coronavirus infection, the disease will worsen, with about 14% of cases developing into severe disease in which patients may need hospitalization and supplemental oxygen. Of the patients with severe infection, about 6% cases become critical and may develop septic shock that can lead to stroke, heart or respiratory failure, failure of other organs or death. Symptoms can worsen in some patients in a matter of days, or even hours.
[0080] As used herein, the term "about" refers to a range of values ± 20%, or ± 15% or ± 10%, or ± 5% of a specified value.
[0081] In addition, in some of the worst cases, the virus can enter lung cells and start replicating and killing the cells. When the immune system creates inflammation to fight the virus, this can sometimes result in a more severe form of pneumonia.
[0082] According to some embodiments, the disease a severe disease. According to some embodiments, coronavirus disease is a severe coronavirus disease. According to some embodiments, a severe disease is a disease associated with at least one severe symptom. According to some embodiments, a severe disease is a disease associated with at least one severe coronavirus symptom. According to some embodiments, a severe disease is a disease with at least one severe symptom associated with coronavirus disease. According to some embodiments, the at least one severe symptom is fever higher than 38°C coupled with shortness of breath. According to some embodiments, the at least one severe symptom is moderate to severe pneumonia.
[0083] According to some embodiments, the pharmaceutical composition is for use in the treatment of a disease selected from tracheitis and pneumonia, which relate to, caused by, and/or induced by COVID-19.
[0084] The term “pharmaceutical composition” is intended to be used herein in its broader sense to include preparations containing the composition used for therapeutic purposes. Accordingly, the pharmaceutical composition contains a therapeutic amount of the active ingredient, namely, the human polyclonal antibodies disclosed herein. The pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically
acceptable carriers, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
[0085] According to any one of the above embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
[0086] The term "pharmaceutically acceptable excipient" as used herein is exchangeable with the term "pharmaceutically acceptable carrier" and refers to any and all solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, surfactants, buffer, a stabilizing agent, and the like that are compatible with pharmaceutical administration. The use of such media and agents in pharmaceutical compositions is well known in the art. The compositions may contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
[0087] As used herein, the term "therapeutically effective amount" is exchangeable with any one of " therapeutically effective dose" or "sufficient/effective amount or dose," and refers to a dose that produces the required therapeutic effects. Specifically, an effective dose generally refers to the amount of the composition disclosed herein sufficient to induce immunity, to prevent and/or ameliorate coronavirus infection, or to reduce at least one symptom associated with the coronavirus infection and/or to enhance the efficacy of another therapeutic composition. An effective dose may refer to the amount of the composition sufficient to delay or minimize the onset of an infection. An effective dose may also refer to the amount of the composition that provides a therapeutic benefit in the treatment or management of infection. In addition, an effective dose may be the amount with respect to the composition alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of a viral infection. An effective dose may also be the amount sufficient to enhance a subject's (in particular, human's) own immune response against a subsequent exposure to virus, specifically, to the coronavirus. The exact effective dose depends on the purpose of the treatment, and is ascertainable by one skilled in the art using known techniques.
[0088] The terms "treating” or “treatment” as used herein refer to taking steps to obtain beneficial or desired therapeutic results. Beneficial or desired therapeutic results include, but are not limited to, alleviation or amelioration of one or more symptoms associated with an infectious disease, delaying or slowing down the propagation of the disease, amelioration,
palliation or stabilization of said disease, among other beneficial results. According to some embodiments, the term “treating” has the meaning of “preventing”. According to any one of the above embodiments, the treatment or prevention of a disease is selected from inhibiting viral replication in a subject, inhibiting viral protein synthesis, preventing and/or inhibiting an increase in cell death in a mammal, and preventing and/or inhibiting death. The term "prophylactic treatment" refers to taking steps to prevent the disease, and in particular infectious disease.
[0089] According to some embodiments, the treatment is passive immunization.
[0090] According to some embodiments, said treatment comprises one or more of reducing the rate of progression of the disease, inhibiting progression of the disease, preventing the disease and attenuating at least one symptom induced or associated with coronavirus disease.
[0091] According to some embodiments, said treatment is prevention the occurrence of coronavirus infection. According to some embodiments said treatment is preventing infection induced by the coronavirus. According to some embodiments said treatment is prophylactic treatment.
[0092] According to some embodiments, the subject in need thereof is a healthy subject and the treatment is prophylactic treatment. According to a further embodiment, the treatment is a prophylactic immunization.
[0093] The term "healthy subject" as used herein refers to a subject not afflicted with coronavirus infection.
[0094] The term "administering" includes any method of delivery of a pharmaceutical composition or agent (i.e., an immunological composition) into a subject's system or to a particular region in, or on, a subject. In certain embodiments, the immunological compositions and/or antibodies disclosed herein are administered via intramuscular, subcutaneous, intradermal, intranasal, oral, transcutaneous or transmucosal administration. As used herein, and as based on context, the terms "administration" or "administrations" encompass a singular or multiple instances, respectively, of the delivery of an agent to a subject such that an immunogenically effective singular delivery as well as a priming delivery (first dose of administration) and a subsequent (second, third, etc., doses or administrations) boosting delivery of an agent(s) are encompassed.
[0095] One skilled in the art readily appreciates that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The examples provided herein are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention.
Examples
[0096] Example 1 : Anti-Coronavirus IgG purified from plasma of convalescent donors
[0097] For preliminary in-vitro evaluations, the anti-coronavirus IgGs were purified using standard Protein G purification process from the plasma of 11 convalescent donors who were coronavirus-free and had a high titer of anti-coronavirus antibodies as determined by a commercial kit (Euroimmun, GmbH).
[0098] For the in-vivo and clinical studies, and further product development, the anti- coronavirus IgG human polyclonal disclosed herein were purified from the plasma of convalescent donors applying the protocol disclosed in WO2018/229760. The convalescent plasma samples subjected to the purification protocol disclosed in WO2018/229760 were initially selected by at least one of the following screening methods: (i) commercial kit anti- SARS-CoV-2 ELISA IgG (Euroimmun), for semi-quantitation of the anti SARS CoV-2 IgG. The preliminary criterion applied in this screening approach, for drug manufacturing, was set as fold positive results >5, later on the criterion was set as > 3.7. (ii) a proprietary screening assay, described in Example 2, which exhibited high correlation (R = 0.9) between the commercial kit (Euroimmun) and the proprietary method (Fig. 3), where the acceptance criterion based on the proprietary method was set as >3.5. It should be noted that in the proprietary method the selection is based on RBD of the SI protein of the SARS CoV-2, as detailed below, while in the commercial kit the selection is based on whole S 1 protein.
[0099] Example 2. Potency of the anti-coronavirus IgG pool
[00100] The potency of the anti-coronavirus IgG pool obtained from convalescent patients was initially determined by the following proprietary ELISA method using relative units against an in-house calibrator or applying a commercial quantitative kit, as detailed below. The in-house calibrator was generated from pool of about 40 plasma samples obtained prior to the emergence of COVID-19 and therefore present the negative response/value. In brief, 96 well plates were coated with a recombinant structural protein of SARS-CoV-2, namely, the spike
protein receptor binding domain (RBD; Sino Biological). The plates were then incubated with the human polyclonal anti-SARS-CoV-2 IgG samples obtained from individual plasma donations which underwent various purification stages of the manufacturing process: (1) manufacturing plasma pool, (2) post DEAE column, (3) post complete cleaning based on the protocol disclosed in WO2018/229760 (also termed Drug Substance; DS), and (4) the latter (clean) diluted as required for clinical applications (also termed Drug Product; DP). Bound antibodies were detected with anti-human IgG conjugated to horse radish peroxidase (HRP) and the resulting absorbance was measured at 450 nm after adding the HRP substrate. The extinction value of the calibrator was used as the cutoff, and is also termed herein negative value. Values above the cutoff were considered positive, namely, having anti-coronavirus capacity and those below as negative, namely, not having the required anti-coronavirus activity. Results were evaluated semi quantitatively by calculating the ratio between the tested sample and the cutoff and named fold positive (Fig. 1 A). Specifically, Figure 1 A exhibits Fold positive results of four sample types: manufacturing plasma pool (sample 62201)- which is the starting material post filtration, in process (partially purified) sample after the first column, namely, the DEAE column (sample 63301), Drug Substance (DS) and drug product (DP). The commercial quantitative kit QuantiVac manufactured by Euroimmun Germany, was used to quantify the amount of anti SARS CoV-2 IgG in international binding antibody unit (BAU) calibrated against WHO standard 20/136. This ELISA plat is coated with SI protein and the detection is performed with anti-human IgG conjugated to horse radish peroxidase (HRP) and the resulting absorbance was measured at 450 nm after adding the HRP substrate. The concentrations of anti SARS CoV-2 IgG, using the commercial kit, were evaluated for four representative batches, expressed as international binding antibody unit per mL (BAU/mL), where for each batch the concentration is provided for the crude plasma pool, the drug substance and the drug product (Fig. IB and Table 1).
[00101] Table 1. Concentrations of anti SARS CoV-2 IgG in 4 representative batches
Sample Batch 111120DV Batch 121120DV Batch 131220AV Batch 010121AV
Plasma pool 286 384 309 428
DS 3272 3062 4795 5935
DP _ 2217 _ 1832 _ 3491 _ 4005 _
[00102] Another preliminary approach for assessing binding of the purified IgG to Spike RBD was monitored by surface plasmon resonance with a BIAcore T200 apparatus (GE Healthcare Life Sciences). Spike protein RBD (Spike) was immobilized on a CM5 chip (GE Healthcare Life Sciences) by amine coupling chemistry using the following protocol: PBST
served as running buffer. After activation with a freshly prepared mixture of hi lly droxysuccinimide (50 mM in water) and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (195 mM in water) for 7.5 min (flow rate 10 pL/min), Spike (2 pg/mL in 150 mM sodium acetate buffer, pH 4.6) was injected for 5 min (flow rate 10 pL/min) to reach 1,300 RU. Remaining activated carboxylic groups were blocked by injection of 1 M ethanolamine hydrochloride, pH 8.6, for 5 min (flow rate 10 pL/min). A total of 1,300 RU of Spike were immobilized onto the CM5 chip by this method. The association of Spike with IgGs was monitored by injecting different concentrations of the IgGs Drug Substance (ranging from 200 nM to 3,200 nM) for 2-4 min at a flow rate of 30 pL/min (Table 2 and Fig. 2). The dissociation of the IgGs from Spike was investigated by stopping their injection. NaOH (10 mM) was used to regenerate the chip.
[00103] For data analysis of the BIACore study Sensograms were fitted to a steady state model (T200 evaluation software). Standard errors are reported as well as X2. Experiments had at least 2 independent biological repeats.
[00104] Table 2: Association, dissociation and affinity constant determined for the drug substance
ka-associate constant; kd dissociation constant; KD - affinity constant
[00105] Example 3. Virus Plaque Reduction Neutralization Test (PRNT)
[00106] PRNT is a serological test that utilizes the ability of a specific antibody to neutralize a virus and prevent the virus from forming plaques in a cell monolayer. The assay involves mixing a constant amount of virus, determined by virus titration performed on the same cell type, prior to each neutralization assay, with dilutions of the serum specimen being tested, followed by plating the mixture onto cells of an appropriate cell line for the individual virus. The neutralization dose 50 (ND50) which is the dose that neutralize 50% of the virus activity, is determined by the number of plaques formed after a few days.
[00107] The PRNT test for SARS-CoV-2 involved the following steps: a plasma sample containing antibody against SARS-CoV-2 was diluted in serial dilutions of 1/10, 1/20, 1/40, 1/80, 1/160, 1/320 in duplicate (or any further dilution depending on the neutralization capability); samples were incubated with SARS-CoV-2 virus for 1 hour (the exact
concentration was determined prior to the assay), then confluent Vero/E6 cells were exposed to/incubated with the mixture of virus + tested sample and overlay media, for 5 days. At the end of the incubation, cells were fixed and stained to expose plaques. The positive control was a known neutralizing serum, while the negative control was only the virus. The dilution of the sample which reduces the number of plaques by 50% compared to the control, neutralization dose 50 (ND50), was calculated and expressed as titer value.
[00108] Preliminary results obtained from the plaque reduction neutralization test (PRNT), are presented in Figure 4A. The following samples were tested:
1. Plasma manufacturing pool sample of R&D batch and of clinical batch (starting material; white columns)
2. Drug substance (DS) sample of R&D batch and of clinical batch (black columns)
3. Drug product (DP) sample of R&D lot and of clinical lot (grey columns)
[00109] The results show the enrichment of the anti-SARS-CoV-2 neutralizing antibodies over the process, starting from ND50s of 542 and 278 in the plasma manufacturing pool samples and ending with ND50s of 3186 and 2989 in the drug products (R&D batch and clinical batch, respectively). The results further indicate that the drug product is about 10 times (an order of magnitude) more potent than the starting material (plasma pool).
[00110] A correlation between the anti SARS CoV-2 IgG concentration determined by a commercial kit (QuantiVac) and the anti SARS CoV-2 IgG neutralization activity determined by PRNT was established, as presented in Figure 4B. 13 samples of drug product and drug substance were tested by both methods and the results were reported as binding antibody unit per mL (BAU/mF) and international unit per mL (IU/mF) for the EFISA and the PRNT respectively. The results indicate a good correlation (R=0.9) between the IgG concentration (binding to SI protein) and the neutralization capability of the anti SARS CoV-2 IgG disclosed herein.
[00111] Neutralization of different SARS CoV-2 variants by the anti SARS CoV-2 IgG product disclosed herein was determined by PRNT. Representative results with two variants, the South African variant (SA) and the British variant UK, are presented in Fig. 4C. In a virus neutralization assay, a standard number of SARS-CoV-2 infectious units of the aforementioned two different variants and the wild-type virus was incubated with serial dilutions of anti SARS CoV-2 IgG drug product (DP). After a one-hour pre-incubation period of the virus/DP mixtures, the mixture was added to Vero cells for an incubation time of one hour. Thereafter
the cells were washed and incubated for additional 16 -24 hours (post infection). Subsequently the cells were fixed and permeabilized followed by incubation with a monoclonal antibody which targets the viral nucleocapsid protein, followed by a secondary anti-mouse IgG peroxidase conjugate and TrueBlue substrate. This formed a blue precipitate on nucleocapsid- positive cells. The 80% and 90% neutralization titers were calculated. The results presented in Figure 4C indicate similar neutralization activity exerted by the anti SARS CoV-2 IgG disclosed herein, where the neutralization capability of the wild type was as assigned the value 1.
[00112] Accordingly, the anti SARS CoV-2 IgG disclosed herein are effective against wild type SARS CoV-2 and variants thereof.
[00113] Example 4: Product characterization
[00114] In parallel to the semi quantitation of the anti SARS Cov-2 IgG described above, the end point titer of the final product (DP) was tested as described in Figure 5. A negative control (plasma sample collected before the pandemic) was tested in a dilution of 1:80 as a reference. From this analysis it was found that the end point titer of the human anti SARS Cov- 2 IgG drug product disclosed herein is approximately 1:6,000 (Fig. 5).
[0001] The different immunoglobulin isotypes were tested in the final product using a method similar to the semi quantitation of anti SARS CoV-2 IgG presented above, where the detection antibody was anti human IgG, IgA, and IgM. The results, presented in Fig. 6, indicate that the predominant isotype in the drug product is IgG with negligible amounts of IgM and IgA. Next, the distribution of the various IgG subclasses in the final product was tested. The results, presented in Fig. 7, indicate that the drug product includes primarily the isotypes IgGl, IgG2, and IgG3, wherein the drug product is practically lacking the IgG4 isotype (exhibits very low levels of this isotype).
[0002] In summary, all of the in-vitro studies presented in Examples 1 to 4 establish, using various methods/assays, that the anti-SARS-CoV-2 IgG product disclosed herein is biologically active.
[00115] In terms of the biological characteristics, the characterization of clinical anti-SARS-CoV-2 IgG DS and DP batches demonstrated consistency of the process used for
manufacturing anti-SARS-CoV-2 IgG for in vivo studies and clinical trials. The results further establish that: i. the comparability of the electrophoretic profile of Anti-SARS-CoV-2 IgG product to IgG under non-reduced conditions, which presents the classic pattern of immunoglobulins: one major band at approximatelyl50-170 kDa representing an intact IgG molecule. ii. the Anti-SARS-CoV-2 IgG product has comparable (relative to plasma) distribution of the IgG, as follows: IgGl: 68%, IgG2: 25%, IgG3: 6% and IgG4: 0.2%. The level of IgG4 is consistently lower than in the plasma in comparison to other IgG subclasses as this IgG subclass is significantly reduced during the manufacturing process. iii. the purification process utilized in the production of the Anti-SARS-CoV-2 IgG product disclosed herein reduces the plasma protein impurities (e.g. transferrin, ceruloplasmin, IgA) to very low levels, resulting in a highly purified product with a very low level of process related impurities. iv. the levels of Factor XIa, plasmin, plasminogen, and PKA are very low. v. the Molecular Size Distribution, Anti-complementary activity (ACA), Anti-A and anti-B haemagglutinins and Anti-D antibodies results comply with the Ph. Eur. requirements.
[00116] Example 5. Anti-Coronavirus hyper-immune IgG and uses thereof for studies in hamster models
[00117] The aims of these studies were to prepare human plasma-derived Anti- SARS-CoV- 2 IgG for systemic injection (intraperitoneal (IP)) to hamsters and evaluate the efficacy of the anti- coronavirus antibodies in terms of protection, and moreover prevention, against coronavirus infection or attenuation of infection and observed clinical signs. Furthermore, the studies' objective was to provide a medical countermeasure against infection and disease caused by the SARS-CoV-2.
[00118] Plasma units from COVID-19 convalescent donors were pooled and IgGs were purified using the aforementioned proprietary manufacturing facility GMP process, to obtain a purified preparation of anti-coronavirus IgGs. The plasma pool titer was determined using
ELISA method and a neutralization cellular assay (Plaque Reduction Neutralization Test, PRNT). Plasma pool was aliquoted and kept frozen for use and establishment of the therapeutic dose. The titer of the drug product (DP), containing the purified IgGs, was determined using PRNT. The resulting DP, also termed herein Anti- SARS-CoV-2 IgG or hyperimmune IgG, was aliquoted and kept frozen for use.
[00119] The terms "hyper-immune IgG" and "hyperimmune IgG" are interchangeable and generally refer to immunoglobulins prepared in a similar way as for normal human immunoglobulin, except that the donors have high titers of antibody against a specific organism or antigen in their plasma.
[00120] In the first study, thirty-six Syrian golden hamsters (males, 5-6 weeks old) were randomly assigned to 5 groups: A, B, C, D and E. Animals were treated intra-peritoneally with anti-SARS-CoV2 human IgG disclosed herein or placebo/vehicle (0.3M glycine) the day before challenge. Animals were challenged with SARS-CoV-2 virus intranasally at a dose of lxlO5 TCID50 (Median Tissue Culture Infectious Dose that signifies the concentration at which 50% of the cells are infected after being exposed to a diluted solution of viral fluid). Animals in the first high dose treatment (55 mg/kg) group were euthanized at 3 days post challenge (dpc), and animals in the placebo (glycine), mock (unchallenged), low dose (14 mg/kg) and a second high dose treatment (55 mg/kg) groups were euthanized at 7 dpc, as summarized in Error! Reference source not found, below.
§Sac day - sacrifice day
[00122] Viral loads in nasal washes, nasal turbinate tissue, trachea and lungs were assessed using a qRT-PCR method for viral RNA titer and tissue culture method for infectious virus titer. Histopathologic alterations of trachea and lungs were evaluated.
Immunohistochemical studies for SARS-CoV- 2 virus were performed on the lungs. Human IgG in the hamster plasma was determined using a commercial ELISA kit.
[00123] Hamsters challenged with SARS-CoV-2 experienced significant body weight loss when compared to the unchallenged hamsters. Virus was detectable in nasal washes, nasal turbinates, trachea and lungs at 3 and 7 dpc. SARS-CoV-2 virus challenge caused histopathologic alteration of the lungs and trachea. Trends of improvement between animals treated with anti-SARS-C0V2 human IgG compared to vehicle were observed in the examined parameters., i.e. reduction in viral RNA in nasal washes on days 1 and 3 and in the lung tissue (right middle lung and the accessary lobes), as well as reduction in infectious virus in nasal washes and in trachea and reduction in percentage of animals demonstrating tracheitis. Human IgG was detectable in 62.5% of the high dose treated animals at 24 h and 4 days after treatment.
[00124] Histopathological observation revealed tracheitis decrease with high dose Anti- SARS-Cov-2 IgG treatment compared to low dose and control vehicle groups (Table 4), where the results reflect the no. of animals having tracheitis relative to the initial no. of animals in the group.
[00126] Thus, the Anti-SARS-Cov-2 IgG prevent SARS CoV-2 is highly effective against tracheitis, which is a condition that can lead to life-threatening complications, if not treated. It is known to attack children and subjects infected with influenza or having pneumonia.
[00127] In the second study, 46 Syrian golden hamsters (male/female) were treated intraperitoneally (IP) with Anti-SARS-Cov-2 IgG in two doses - low dose, 55 mg/kg and high doses 330 mg/kg (x6 fold of the low dose), and control vehicle (0.3 M glycine) one day before challenge (prophylactic treatment) and one day post-challenge. Animals were challenged, via
intranasal (IN) route with SARS-CoV-2 virus at a dose of 6xl03 PFU per hamster. The groups and treatments are summarized in Table 5.
[00129] Fig. 8 shows the body weight of the aforementioned 6 groups: Group 1 - circle, solid line, Group 2 - square, Group 3 - downward triangle, Group 4 - diamond, Group 5 - circle broken line, Group 6 - triangle. The results indicate that all hamsters challenged with the virus SARS-CoV-2 experienced body weight loss. However, prophylactic treatment with the anti SARS-CoV-2-IgG product disclosed herein prevented the significant decrease in body weight, resulting in about 7% reduction at the 7th day post challenge (Fig. 8, circle solid line), compared to about 12% to 15% reduction of untreated groups (vehicle; Fig. 8 downward triangles and squares). Furthermore, post challenge treatment with the anti SARS-CoV-2-IgG product disclosed herein at the high dose (330 mg/kg) attenuated the reduction in body weigh from 15% (vehicle) at day 7 post challenge to 8 - 10% (Fig. 8 upward triangle and circle broken line).
[00130] Thus, the anti SARS-CoV-2-IgG product disclosed herein prevent damages caused by SARS CoV-2 virus and hence can be used as prophylactic treatment.
[00131] Example 6. Uses of purified coronavirus IgG for preclinical studies in a ferret model
[00132] Ferrets; -50% male/female (neutered/spayed); 30-40 weeks old are administered anti-viral IgG IV, one day before viral infection. The study includes 4 groups according to Table 6:
[00133] Table 6. Study groups and treatments
[00134] The ferrets are challenged intranasally (0.25 ml/nare), with a viral dose of: lxlO6 TCID50 SARS-CoV-2. Nasal wash samples are taken for viral RNA detection and live virus determination. Blood samples are taken for ELISA analysis. Weight clinical signs and temperature of the animals are measured during the study. Necropsy and tissue collections (lung, nasal turbinates, and trachea) are conducted on day 7 post infection for histology and pathology assessments.
[00135] Example 7. Clinical study: Anti-SARS-CoV-2 for treatment of COVID-19 patients hospitalized with pneumonia
[00136] A phase 1/2 open label, single arm study to evaluate the safety, pharmacokinetics and pharmacodynamics of single dose Anti-SARS-CoV-2 was conducted with COVID-19 hospitalized patients with pneumonia. This phase 1/2 open label single arm study was designed to assess the safety pharmacokinetics and pharmacodynamics of the anti-coronavirus human polyclonal antibodies disclosed herein (also termed "Anti-SARS-CoV-2") in non-ventilated patients with pneumonia within 10 days of symptom onset. This population is also referred to as COVID-19 patients with moderate to severe disease. A total of 12 eligible patients were enrolled and received the polyclonal antibodies disclosed herein, namely, Anti-SARS-CoV-2 at a single dose of 4 g IgG, via intravenous infusion.
[00137] Study Population: Hospitalized COVID-19 patients aged >18 years of age with pneumonia, within 10 days of symptom onset, who did not require mechanical ventilation at enrollment. Inclusion and exclusion criteria for enrollment are listed below. The specific details of the study population (n = 12) is provided in Table 7.
[00138] Inclusion Criteria for Enrollment:
1. Age > 18 years
2. Laboratory confirmed SARS-CoV2 Infection by nasopharyngeal RT-PCR.
3. Hospitalized for COVID-19 with pneumonia.
4. Dosing should be within 10 days of symptom start.
5. Able and willing to sign Informed Consent Form (ICF).
[00139] Exclusion Criteria for Enrollment:
1. History of hypersensitivity to plasma products and/or severe IgA deficiency (< 7 mg/dL)
2. Requirement of high flow oxygen devices, or non-invasive ventilation or mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) at screening
3. Cardiovascular instability
4. History of thrombo-embolic events
5. Acute renal failure or creatinine >2 mg/dL or eGFR <30 mL/min
6. History of lung transplantation
7. Major surgery (abdominal and chest) within the last 4 weeks
8. Severe chronic background disease, per investigator's judgement for example, Cirrhosis grade C, Dialysis, cardiac insufficiency (NYHA III), pulmonary disease (FEVi<50 percent of predicted) etc.
9. Pregnancy or lactation
10. Treatment with plasma units or immunoglobulin preparations within the last 4 weeks
11. Participation in another pharmaceutical interventional clinical study within 4 weeks from screening
[00141] Duration of the study was 84 days. Treatment was initiated on day 1, and each patient was followed up until day 84.
[00142] Primary Outcome: The treatment emergent adverse events (TEAE), adverse events (AE), adverse reactions (AR), serious adverse events (SAE) and deaths up to day 28 are discussed below and also presented in Table 8.
[00144] Typically, an adverse event (AE) is any untoward medical occurrence in a patient or clinical study patient, temporally associated with the use of investigational product, whether or not considered related to the investigational product. A serious AE (SAE) is commonly defined as any untoward medical occurrence that either: results in death, is life
threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity and/or is a congenital anomaly/birth defect.
[00145] Adverse Reaction is treatment related adverse event classified as “Probably”, “Possibly” related or missing relationship to study drug, wherein adverse events are presented in the following scheme: number of events; number of patients and corresponding percentage of patients (12 patients = 100%), wherein the percentage is presented within brackets.
[00146] Deaths: One patient enrolled in the study experienced COVID-19 disease deterioration, and subsequently died. The deterioration was considered by the investigator to be not related to the study drug.
[00147] A. Duration of hospital and ICU stays and mechanical ventilation
[00148] Table 9 summarizes the hospital duration, ICU and mechanical ventilation. Table 9: Covid-19 Related Hospitalization Duration
[00149] C. 6-Ordinate Clinical Status score
[00150] Each patient was given a score from 1-6 based on the clinical status at the time of assessment, as shown in Table 10. The assessment was done at screening (eligible patients have
a score of 3-5), and at days 1, 7, 14, 21, 28, 56 and 84. The 6-Ordinate scores are described in Table 10.
[00151] Table 10: 6-Ordinate Clinical Status score scale
Status Score
Death 1
Hospitalized, on invasive mechanical ventilation or extracorporeal 2 membrane oxygenation (ECMO)
Hospitalized, on non-invasive ventilation or high flow oxygen devices 3
Hospitalized, requiring supplemental oxygen 4 Hospitalized, not requiring supplemental oxygen 5 Discharged alive 6
[00152] At baseline, of the 12 (100%) hospitalized patients, two patients had scores of 4 (16.7%) and ten patients (83.3%) had a score of 5. On Day 3, four patients (33%) were discharged (score 6), six patients (50%) had a score of 5 and two patients (16.7%) had a score of 4. On day 7, eight patients (66.7%) were discharged, two patients (16.7%) had a score of 5, one patient (8.3%) had a score of 4 and one patient (8.3 %) had a score of 3. On day 14 eleven patients (91.7%) were discharged and one patient (8.3%) had a score of 2.
[00153] ICU and Mechanical Ventilation (Covid-19 Related Health Encounters)
[00154] Only one patient (designated 03-01) was admitted to the ICU and required mechanical ventilation. ICU admission was due to an SAE of acute respiratory failure related to Covid-19.
[00155] Neutrophil to Lymphocyte Ratio:
[00156] The neutrophil to lymphocyte ratio is a risk marker for severe COVID-19 disease, with a value of above 3.13 at age >50 marking a 50% risk of severe disease. At screening, 9/12 patients displayed a ratio of 3.13 and above, indicating that about half of the patients were at risk of severe disease. At day 14 not all patients were available for blood sampling however, all patients except for one were discharged from the hospital and those who were tested displayed a marked reduction in the neutrophil to lymphocyte ratio, to below 3.13. The patient for whom the ratio increased experienced a concomitant deterioration and eventually succumbed to the disease. The neutrophil to lymphocyte ratios are of the 12 patients are provided in Table 11.
[00157] Table 11: Ratio Neutrophils/Lymphocytes
[00158] In summary, the results of the clinical study indicate that the Anti-SARS-CoV-2 human polyclonal antibodies disclosed herein has a good safety profile with no evidence of infusion associated adverse events or anaphylaxis. Specifically, adverse reactions were not documented, and serious adverse event were minor compared to the entire group of patients (16.7%). Moreover, the clinical condition of 11 of the 12 patients (91.7%) improved after a single administration of the antibodies and were discharged from hospital after a median duration of 5 days from antibodies administration (which is equivalent to 6 days from hospitalization).
[00159] While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include ah such embodiments and equivalent variations.
[00160] Unless otherwise defined, ah technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of conflict, the patent specification, including definitions, governs. As used herein, the indefinite articles “a” and “an” mean “at least one” or “one or more” unless the context clearly dictates otherwise.
[00161] Unless specifically stated otherwise, as apparent from the disclosure, it is appreciated that, according to some embodiments, terms such as “processing”, “computing”,
“calculating”, “determining”, “estimating”, “assessing”, “gauging” or the like, may refer to the action and/or processes of a computer or computing system, or similar electronic computing device, that manipulate and/or transform data, represented as physical (e.g. electronic) quantities within the computing system’s registers and/or memories, into other data similarly represented as physical quantities within the computing system’s memories, registers or other such information storage, transmission or display devices.
Claims
1. A method for treating COVID-19 disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising anti-coronavirus human polyclonal antibodies.
2. The method according to claim 1, wherein the anti-coronavirus human polyclonal antibodies comprise anti-coronavirus human polyclonal IgG.
3. The method according to claim 1, wherein anti-coronavirus human polyclonal antibodies are derived from the plasma of convalescent human donors.
4. The method according to claim 3, wherein the convalescent human donors are convalescent vaccinated human donors.
5. The method according to claim 1 , wherein the anti-coronavirus polyclonal antibodies are derived from the plasma of vaccinated human donors.
6. The method according to claim 1, wherein the COVID-19 disease comprises pneumonia and/or tracheitis.
7. The method according to claim 1, wherein the pharmaceutical composition is in a liquid form.
8. The method according to claim 7, wherein the pharmaceutical composition is for intravenous use.
9. The method according to claim 1, wherein the anti-coronavirus human polyclonal antibodies have a binding capacity to coronavirus, or to antigen associated therewith, which is at least 6-fold higher than the binding capacity of negative plasma samples derived from one or more human donors who were not infected by coronavirus and/or do not have antibodies to determinants associated with coronavirus.
10. The method according to claim 1, wherein the anti-coronavirus human polyclonal antibodies neutralize SARS-COV-2 and variants thereof.
11. The method according to claim 1, wherein said administering comprises at least one administration.
12. The method according to claim 1, wherein said administering comprises a plurality of administrations.
13. The method according to claim 1, wherein said treatment is prophylactic treatment.
14. A pharmaceutical composition comprising anti-coronavirus human polyclonal antibodies method for the treatment of COVID-19 disease.
15. The pharmaceutical composition according to claim 14, wherein the anti- coronavirus human polyclonal antibodies comprise anti-coronavirus human polyclonal IgG.
16. The pharmaceutical composition according to claim 14, wherein the anti- coronavirus human polyclonal antibodies are derived from the plasma of convalescent human donors, vaccinated convalescent human donors or vaccinated human donors.
17. The pharmaceutical composition according to claim 14, wherein the COVID-19 disease comprises pneumonia and/or tracheitis.
18. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is in a liquid form.
19. The pharmaceutical composition according to claim 18, for intravenous use.
20. The pharmaceutical composition according to claim 14, wherein the anti- coronavirus human polyclonal antibodies have a binding capacity to coronavirus, or to antigen associated therewith, which is at least 6-fold higher than the binding capacity of negative plasma samples derived from one or more human donors who were not infected by coronavirus and/or do not have antibodies to determinants associated with coronavirus.
21. The pharmaceutical composition according to claim 14, wherein said treatment is prophylactic treatment.
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US202063042038P | 2020-06-22 | 2020-06-22 | |
US63/042,038 | 2020-06-22 | ||
US202063109916P | 2020-11-05 | 2020-11-05 | |
US63/109,916 | 2020-11-05 |
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EP4292602A1 (en) * | 2022-06-14 | 2023-12-20 | Prevor International | Intranasal administration of a polyclonal blood derivative directed against a pathogen agent for the prevention and/or treatment of an airborne disease |
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Cited By (2)
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EP4292602A1 (en) * | 2022-06-14 | 2023-12-20 | Prevor International | Intranasal administration of a polyclonal blood derivative directed against a pathogen agent for the prevention and/or treatment of an airborne disease |
WO2023242229A1 (en) * | 2022-06-14 | 2023-12-21 | Prevor International | Intranasal administration of a polyclonal blood derivative directed against a pathogen agent for the prevention and/or treatment of an airborne disease |
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