WO2017149528A1 - Intrauterine therapy and prophylaxis of infectious diseases in a mammal fetus - Google Patents
Intrauterine therapy and prophylaxis of infectious diseases in a mammal fetus Download PDFInfo
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- WO2017149528A1 WO2017149528A1 PCT/IL2017/050243 IL2017050243W WO2017149528A1 WO 2017149528 A1 WO2017149528 A1 WO 2017149528A1 IL 2017050243 W IL2017050243 W IL 2017050243W WO 2017149528 A1 WO2017149528 A1 WO 2017149528A1
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
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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
- C07K16/1081—Togaviridae, e.g. flavivirus, rubella virus, hog cholera virus
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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
- C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
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- 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
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- Methods for treating a disease or disorder in a mammal fetus caused by a virus of Flavivirus genus comprises intrauterine administration of an active agent such as antiviral antibodies.
- Viral infections during gestation represent a major cause of fetal morbidity and mortality.
- the clinical manifestations of such infections vary depending on the viral agent and gestational age at the exposure.
- the risk of fetal infection, and the associated congenital sequelae is usually inversely related to gestational age at the time of maternal infection.
- Infections known to produce congenital defects have been categorized with the acronym TORCH (Toxoplasma, Rubella, Cytomegalovirus, Herpes and others) based on the pathogens first implicated and including a group defined "others", which is rapidly expanding.
- TORCH Toxoplasma, Rubella, Cytomegalovirus, Herpes and others
- viruses which gave the greatest cause for concern during gestation due to their congenital sequela were rubella, cytomegalovirus, and herpes simplex virus.
- the group of "other" pathogens, including viruses now known to cause congenital infections has expanded to include parvovirus B19, varicella-zoster virus, measles virus, enteroviruses, adenovirus, human immunodeficiency virus, hepatitis E virus, West Nile virus and most recently the Zika virus.
- Cytomegalovirus is the most common virus known to be transmitted from mother to fetus in utero, affecting approximately 0.5%-1.5% of births. Approximately 40% of maternal CMV infections during gestation result in congenital infection of the fetus. Depending on the population studied, the frequency of herpes infection in neonates is estimated to be between 1 per 1700 to 1 per 12,500 live births. The rate of Herpes simplex virus 2 seroconversion during gestation is estimated to be 0.2%-4%. The estimated incidence of primary B19V infection in gestation ranges from l%-5% and Varicella occurs in approximately 1-7 per 10,000 pregnancies.
- ZIKV Zika vims
- Flaviviridae virus family and the flavivirus genus. In humans, it causes a disease known as Zika fever. It is related to dengue, yellow fever, West Nile and Japanese encephalitis, viruses that are also members of the virus family Flaviviridae. ZIKV is spread to people through mosquito bites. The most common symptoms of ZIKV disease (Zika) are fever, rash, joint pain, and red eye. The illness is usually mild with symptoms lasting from several days to a week. Today there is still no approved vaccine to prevent, or medicine to treat, Zika virus.
- Zika virus can pass from a pregnant woman to her fetus during pregnancy or around the time of birth.
- Zika infection in pregnancy is a cause of microcephaly and other severe brain defects to the fetus.
- Other problems include eye defects, hearing loss, impaired growth, fetal loss, cognition disability and Guillain-Barre -Syndrom (GBS)
- GGS Guillain-Barre -Syndrom
- the placenta has an important role in the fetal immune system, not only recognizing microorganisms but also initiating an immune response. Research has shown that the trophoblast, the cellular unit of the placenta, expresses antimicrobial (human beta defensins 1 and 3), antiviral proteins (secretory leukocyte protease inhibitor - SLPI), cytokines (TGF-B) and Toll like receptors to prevent transmission of infection. It has been suggested that the placenta serves as a regulator of trafficking between the fetus and the mother and not a barrier. Some pathogens are able to take advantage of this phenomenon and reach the fetus via transplacental passage .
- the fetus does not have a fully function immune system and develops functionality step by step as gestation progresses to birth.
- the fetus is protected by the innate immune system, also known as the nonspecific immune system or inborn immunity system.
- the innate immune system which protects the fetus from infection, develops relatively early in the gestation.
- the cells of the innate system recognize and respond to pathogens in a generic way and do not confer long-lasting or protective immunity to the fetus
- PAMPs pathogen-associated molecular patterns
- Macrophages are one of the major players of the fetus immune system. Macrophages are the most efficient phagocytes and can phagocytose substantial numbers of bacteria or other cells or microbes. Binding of the bacterial molecules to receptors on the surface of a macrophage triggers the latter to overcome and destroy the bacteria through the generation of a "respiratory burst". Pathogens also stimulate the macrophage to produce chemokines, which summon other cells to the site of infection. It has been shown that the embryo macrophages can be active and protect from viral infection early in the gestation (Florent Ginhoux. 2014, Nature Reviews Immunology 14,392-404).
- Neutrophils similarly to macrophages, attack pathogens by activating a respiratory burst.
- the main products of the neutrophil respiratory burst are strong oxidizing agents including hydrogen peroxide, free oxygen radicals and hypochlorite.
- Neutrophils are the most abundant type of phagocyte, normally representing 50-60% of the total circulating leukocytes, and are usually the first cells to arrive at the site of an infection.
- Neutrophils also trigger the other parts of the immune system by releasing factors that summon additional leukocytes and lymphocytes. Macrophages and other cells of the innate immune system produce cytokines such TNF, HMGB1, and IL-1 that mediate the inflammatory response.
- the Fc receptor is a protein found on the surface of certain cells that contribute to the protective functions of the immune system including, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells. Its name is derived from its binding specificity for a part of an antibody known as the Fc (Fragment, crystallizable) region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens.
- FcRn mediates a passive transfer of the maternal IgG across the placenta and neonatal intestinal walls of mammals, thereby conferring passive immunity to the offspring before and after birth (Rath T. et al., Front. Immunol. 2015, 5:664; and Wang Y. et al., Am J Reprod Immunol. 2016 Feb;75(2):81-5).
- FcRn Neonatal Fc receptor
- FcRn has been shown to mediate the bidirectional transport of IgG across all polarized epithelial barriers including those of the gastrointestinal and respiratory tract, the placenta, and the genitourinary system including kidneys (Spiekermann et al., J Exp Med(2002) 196:303-10; Bai Y et al., Proc Natl Acad Sci USA (2011) 108(45): 18406-11; and Claypool et al., J Biol Chem (2002) 277:28038-50).
- Determination whether the fetus has been infected may require multiple tests such as virus isolation from the amniotic fluid, qualitative search for pathogenic DNA in amniotic fluid and pathogenic DNA quantification by quantitative PCR. The combination of these tests may be required to complete the diagnosis.
- RT-PCR and serology assays can be performed on maternal serum or plasma, and/or RT-PCR can be performed on amniotic fluid. Amniocentesis will be offered to pregnant women in certain cases.
- the current strategy in case of maternal infection during the pregnancy, is to diagnose and treat the pregnant woman hoping that the woman will not pass the infection to the fetus. In case of fetal infection, pregnancy termination will be suggested.
- WO 2011/132191 discloses a method for treatment of a uterine infection, the method comprising intrauterine administration to a female mammalian animal in need of treatment of uterine infection, an amount of at least one casein peptide.
- Duff P. (Perinatology 2010; 1 : 1-6) describes administration of anti-CMV antibodies to 31 pregnant women who were found to carry fetuses infected with CMV. Nine of the 31 received one or two additional infusions of hyperimmune globulin into either the amniotic fluid or umbilical cord because of persistent fetal abnormalities on ultrasonography.
- the present invention discloses that non-maternal passive immunization of a fetus is beneficial in the prevention and/or treatment of intrauterine infections that endanger the fetus.
- the present invention provides a pharmaceutical composition comprising an effective amount of an active compound, for use in treatment of a disease in a mammal fetus caused by a virus of Flavivirus genus, wherein said active compound is capable of treating the disease and said pharmaceutical composition is administered intrauterinally.
- said pharmaceutical composition is administered into the amniotic sac.
- the active agent is an antibody.
- the virus is Zika virus and the antibodies are capable of biding to Zika virus.
- the fetus is a human fetus.
- the fetus is a healthy fetus and the treatment is a prophylactic immunization.
- the fetus is infected by a virus of Flavivirus genus such as Zika virus and the treatment is a passive immunization.
- the intrauterinal administration is selected from intra-amniotic administration, intraumbilical cord administration, intra-placental vasculature administration, intrafetus administration and administration by vaginal procedure.
- the present invention provides a method for the treatment of a disease or disorder caused by a virus of Flavivirus genus in a mammal fetus comprising administering intrauterinally a pharmaceutical composition comprising an effective amount of an active compound capable of treating the disease.
- the treatment is a prophylactic treatment.
- prophylactic treatment comprises administrating the composition before a delivery to prevent contagion during the delivery.
- the delivery is vaginal delivery or via Cesarean section.
- the active compound is an anti-viral compound.
- the active compound is an antibody.
- the antibody is a polyclonal antibody.
- the antibody is a monoclonal antibody.
- the active compound may be administered to the amniotic sac, to the umbilical cord or directly to the fetus, e.g. intramuscularly.
- the administration may be single or multiple administration.
- the treatment or immunization is preventive, i.e. prophylactic treatment or immunization.
- the present invention provides a method for passive immunization of a mammal fetus comprising administering intrauterinally a pharmaceutical composition comprising an effective amount of an antibody or fragment thereof, wherein the antibody or fragment thereof binds specifically to the pathogen.
- the antibody or the fragment thereof is non-maternal monoclonal or polyclonal antibody.
- the present invention provides a pharmaceutical composition comprising an effective amount of an active compound, for use in treatment of a disease in a mammal fetus caused by a virus of Flavivirus genus, wherein said active compound is capable of treating the disease and said pharmaceutical composition is administered intrauterinally.
- treating refers to taking steps to obtain beneficial or desired results, including clinical results.
- beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms associated with an infectious disease, delay or slowing of that disease, amelioration, palliation or stabilization of that disease, and other beneficial results.
- the term “treating” has the meaning of "preventing”.
- the treating or prevention of a disease is selected from inhibiting viral replication in a mammal embryo, inhibiting viral protein synthesis, preventing and/or inhibiting an increase in cell death in a mammal embryo and preventing and/or inhibiting an increase in fetus and later newborn death.
- prophylactic treatment refers to taking steps to prevent the disease, and in particular infectious disease.
- prophylactic treatment comprises treatment before a delivery to prevent contagion during the delivery.
- the delivery is vaginal delivery or Cesarean section.
- the term "effective amount” as used herein refers to a sufficient amount of the active compound that, when administered, will have the intended therapeutic effect.
- compositions and “pharmaceutically acceptable composition” are used herein interchangeably and refer to a composition comprising the active compound as disclosed herein below, e.g. antibodies or fragment thereof, formulated together with one or more pharmaceutically acceptable carriers. Such composition may further comprise one or more active agent.
- fetus and “embryo” are used herein interchangeable and refer to a multicellular diploid eukaryote during the embryogenesis, the prenatal development, pregnancy or gestation and during the delivery process, e.g. vaginal delivery or Cesarean section. This term refers to the developing organism during the whole process of prenatal development during the pregnancy and to the organism during the delivery such as vaginal delivery or Cesarean section.
- the fetus is a human fetus. In human, the prenatal development is typically divided into three trimesters. Therefore in one embodiment, the term “fetus” refers to a fetus during the first, second and the third trimesters.
- intrauterine administration refers to administration into any part of the uterus, administration within the interior of the uterus, and to any body located within the uterus such as placenta or fetus, such that the active compound reaches the fetus.
- the intrauterine administration is invasive. Examples of such administration is administration during amniocentesis, amniotic sac puncture and/or injection and injection into the placental vasculature or umbilical cord, e.g. into umbilical vein.
- the administration encompasses also administration into the fetal side of the maternal -fetal interface. Direct administration to the fetus is encompassed as well.
- amniocentesis refers to a medical procedure during which the amniotic sac is punctured. During the procedure amniotic fluid may be taken for diagnostic purposes. Therefore in one embodiment, the administration of an active agent is performed during the amniocentesis procedure in which amniotic fluid is taken.
- the administration, and in particular amniocentesis may be performed with or without a guidance.
- the guidance are optical, ultrasound and injection guides.
- the virus of Flavivirus genus is selected from Zika virus, Yellow fever virus, Dengue fever virus, Japanese encephalitis virus, West Nile encephalitis virus, virus causing to Kyasanur Forest, Murray Valley encephalitis virus, St. Louis encephalitis virus, Usutu encephalitis virus, Tick-borne encephalitis virus, and Omsk hemorrhagic fever virus.
- said viral infection correlates with an increase in cell death in an animal or in a human infected by said virus.
- the infection and in particular viral infection is correlated with inhibiting fetus brain development.
- Dengue virus is a mosquito-borne (Aedes aegypti/ Aedes albopictus) member of the family Flaviviridae (positive-sense, single- stranded RNA virus).
- the dengue virus genome encodes ten genes and is translated as a single polypeptide which is cut into ten proteins: the capsid, envelope, membrane, and nonstructural proteins (NS 1, NS2A, NS2B, NS3, SN4A, NS4B, and NS5 proteins).
- the virus' main antigen is DENe, which is a component of the viral surface and is thought to facilitate the binding of the virus to cellular receptors (Heinz et al, Virology. 1983, 126:525).
- the dengue virus E protein includes a serotype-specific antigenic determinant and determinants necessary for virus neutralization (Mason et al, Gen Virol. 1990, 71 :2107-2114).
- the dendritic cells After inoculation, the dendritic cells become infected and travel to lymph nodes. Monocytes and macrophages are also targeted shortly thereafter. Generally, the infected individual will be protected against homotypic reinfection for life; however, the individual will only be protected against other serotypes for a few weeks or months (Sabin, Am J Trop Med Hyg. 1952, 1 :30-50). In fact, DHF/DSS is generally found in children and adults infected with a dengue virus serotype differing from their respective primary infection. Thus, it is necessary to develop polyclonal antibody that provides immunity to all four serotypes.
- Zika virus is enveloped and icosahedral with a non-segmented, single-stranded, positive sense RNA genome. It is most closely related to the Spondweni virus and is one of the two viruses in the Spondweni virus clade .
- the virus was first isolated in 1947 from a rhesus monkey in the Zika Forest of Kenya, Africa and was isolated for the first time from humans in 1968 in Nigeria. From 1951 through 1981, evidence of human infection was reported from other African countries such as Philippine, Indonesia, Central African Republic, Sierra Leone and Gabon, as well as in parts of Asia including India, Malaysia, the Philippines, Thailand, Vietnam and Indonesia.
- mosquitoes It is transmitted by mosquitoes and has been isolated from a number of species in the genus Aedes -Aedes aegypti, Aedes africanus, Aedes apicoargenteus, Aedes furcifer, Aedes luteocephalus and Aedes vitattus. Studies show that the extrinsic incubation period in mosquitoes is about 10 days.
- the vertebrate hosts of the virus include monkeys and humans.
- the most widespread outbreak of Zika fever caused by the Zika virus, is ongoing primarily in the Americas. The outbreak began in April 2015 in Brazil, and subsequently spread to other countries in South America, Central America, and the Caribbean.
- the Zika virus was first linked with newborn microcephaly during the Brazil Zika virus outbreak.
- 2017. there were 2,782 cases of microcephaly compared with 147 in 2014 and 167 in 2013.
- the Brazilian Health Ministry has reported 4783 cases of suspected microcephaly as of January 30, an increase of more than 1000 cases from a week earlier. Confirmation of many of the recent cases is pending, and it is difficult to estimate how many cases went unreported before the recent awareness of the risk of virus infections. What is important is not only the number of cases but also the clinical manifestation of the cases. Brazil is seeing severe cases of microcephaly, which are more likely to be paired with greater developmental delays. Most of what is being reported out of Brazil is microcephaly with other associated abnormalities.
- Zika virus has also been associated with an increase in a rare condition known as Guillain-Barre, where the infected individual becomes essentially paralyzed.
- Guillain-Barre a rare condition known as Guillain-Barre
- GBS Guillain-Barre syndrome
- active agent and “active moiety” are used herein interchangeable and refer to any molecule, drug, compound, composition of matter or mixture thereof which provides the desired pharmacologic effects, e.g. treating the disease caused by a virus of Flavivirus genus.
- the active agent is an antibody or fragment thereof capable of treating the disease.
- the active agent is a small molecule capable of treating the disease.
- the active agent is antibody or fragment thereof that binds specifically to the virus of Flavivirus genus.
- the treatment comprises a passive immunization of the mammal fetus.
- the present invention provides a pharmaceutical composition comprising an effective amount of antibodies which bind specifically to a virus of Flavivirus genus, for use in passive immunization of a mammal fetus.
- passive immunization and “passive vaccination” is used herein interchangeably and refers to a process of providing or administering an exogenous antibody or a fragment thereof to an organism in order to treat an infectious disease caused by a pathogen or to prevent a contagion by that pathogen.
- exogenous antibody refers to an antibody or a fragment thereof that is not originated from the fetus. Exogenous antibody may be of maternal origin or of non-maternal origin. Thus according to one embodiment, the antibody is an exogenous antibody. [0055] According to some embodiments, the antibody is a non-maternal antibody or a fragment thereof. Therefore, according to some embodiments, the treatment according to present invention encompasses non-maternal immunization of a fetus.
- non-maternal immunization refers to immunization by an antibody or a fragment thereof that is not originated from the mother. Therefore, in one embodiment, the treatment according to the present invention comprises administering an antibody or fragment thereof with a proviso that said antibody is a non-maternal antibody, i.e. is not originated from the mother.
- the antibody is a polyclonal antibody or a fragment thereof. According to a further embodiment, the antibody is a non-maternal polyclonal antibody or a fragment thereof. According to some embodiments, the antibody is a monoclonal antibody or a fragment thereof. According to a further embodiment, the antibody is a non-maternal monoclonal antibody or a fragment thereof.
- the antibody is enriched maternal antibody, i.e. enriched antibody isolated from the mother.
- enriched indicates that the amount or the concentration of the antibody administered intrauterally is higher than that reaching the uterus via maternal immunization, i.e. by a transfer of maternal IgG via placenta.
- the maternal antibody is purified from the maternal blood or plasma.
- antibody and “antibodies” are used here interchangeably in its broadest sense and includes monoclonal antibodies (including full length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies, multi-specific antibodies (e.g., bi- specific antibodies), and antibody fragments long enough to exhibit the desired biological activity.
- An antibody is a molecule comprising at least the antigen-binding portion of an antibody.
- Antibody or antibodies according to the invention include intact antibodies, i.e. monoclonal antibodies (mAbs), as well as proteolytic fragments thereof, such as the Fab or F(ab') 2 fragments. Single chain antibodies also fall within the scope of the present invention.
- Antibodies, or immunoglobulins comprise two heavy chains linked together by disulfide bonds and two light chains, each light chain being linked to a respective heavy chain by disulfide bonds in a "Y" shaped configuration.
- Proteolytic digestion of an antibody yields Fv (Fragment variable) and Fc (Fragment crystalline) domains.
- the antigen binding domains, Fab include regions where the polypeptide sequence varies.
- the term F (ab') 2 represents two Fab' arms linked together by disulfide bonds.
- the central axis of the antibody is termed the Fc fragment.
- Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains (CH).
- Each light chain has a variable domain (VL) at one end and a constant domain (CL) at its other end, the light chain variable domain being aligned with the variable domain of the heavy chain and the light chain constant domain being aligned with the first constant domain of the heavy chain (CHI).
- VL variable domain
- CL constant domain
- CHI first constant domain of the heavy chain
- the variable domains of each pair of light and heavy chains form the antigen-binding site.
- the domains on the light and heavy chains have the same general structure and each domain comprises four framework regions, whose sequences are relatively conserved, joined by three hyper-variable domains known as complementarity determining regions (CDRs 1-3). These domains contribute specificity and affinity of the antigen-binding site.
- the isotype of the heavy chain determines immunoglobulin class (IgG, IgA, IgD, IgE or IgM, respectively).
- the light chain is either of two isotypes (kappa, ⁇ or lambda, ⁇ ) found in all antibody classes.
- polyclonal antibody denotes a mixture of different antibody molecules which react with more than one immunogenic determinant of an antigen.
- polyclonal antibody encompasses a polyclonal antibody isolated or purified from mammalian blood, secretions, or other fluids, or from eggs, as well as a mixture of different monoclonal antibodies, and finally a polyclonal antibody may be produced as a recombinant polyclonal antibody.
- mAb monoclonal antibody
- Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
- the modifier "monoclonal” is not to be construed as requiring production of the antibody by any particular method. mAbs may be obtained by methods known to those skilled in the art.
- the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al., Nature 1975, 256, 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
- the "monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature 1991, 352, 624-628 or Marks et al., J. Mol. Biol., 1991, 222:581-597, for example.
- the mAbs of the present invention may be of any immunoglobulin class including IgG, IgM, IgE, IgA.
- a hybridoma producing a mAb may be cultivated in-vitro or in-vivo.
- High titers of mAbs can be obtained by in-vivo production where cells from the individual hybridomas are injected intra-peritoneally into pristine-primed Balb/c mice to produce ascites fluid containing high concentrations of the desired mAbs.
- mAbs of isotype IgM or IgG may be purified from such ascites fluids, or from culture supernatants, using column chromatography methods well known to those of skill in the art.
- the invention also provides conservative amino acid variants of the antibody molecules according to the invention. Variants according to the invention also may be made that conserve the overall molecular structure of the encoded proteins. Given the properties of the individual amino acids comprising the disclosed protein products, some rational substitutions will be recognized by the skilled worker. Amino acid substitutions, i.e. "conservative substitutions” may be made, for instance, on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved.
- antibody analog refers to an antibody derived from another antibody by one or more conservative amino acid substitutions.
- antibody variant refers to any molecule comprising the antibody of the present invention.
- fusion proteins in which the antibody or an antigen-binding-fragment thereof is linked to another chemical entity is considered an antibody variant
- Antibody fragments comprise only a portion of an intact antibody, generally including an antigen binding site of the intact antibody and thus retaining the ability to bind antigen.
- Examples of antibody fragments encompassed by the present definition include: (i) the Fab fragment, having VL, CL, VH and CHI domains; (ii) the Fab' fragment, which is a Fab fragment having one or more cysteine residues at the C-terminus of the CHI domain; (iii) the Fd fragment having VH and CHI domains; (iv) the Fd' fragment having VH and CHI domains and one or more cysteine residues at the C-terminus of the CHI domain; (v) the Fv fragment having the VL and VH domains of a single arm of an antibody; (vi) the dAb fragment (Ward et al., Nature 1989, 341, 544-546) which consists of a VH domain; (vii) isolated CDR regions; (viii) F(ab') 2 fragments
- Single chain antibodies can be single chain composite polypeptides having antigen binding capabilities and comprising amino acid sequences homologous or analogous to the variable regions of an immunoglobulin light and heavy chain i.e. linked VH-VL or single chain Fv (scFv).
- immunoglobulin light and heavy chain i.e. linked VH-VL or single chain Fv (scFv).
- the polyclonal antibody or the antibody fragment according to the present invention is selected from non-human mammalian or human antibody.
- the monoclonal antibody or the antibody fragment according to the present invention is selected from the group consisting of non-human mammalian, human, humanized and chimeric antibody or the antibody fragment.
- human antibody refers to an antibody which possesses an amino acid sequence which corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art.
- humanized antibody refers to an antibody that has its CDRs (complementarily determining regions) derived from a non-human species immunoglobulin and the remainder of the antibody molecule derived mainly from a human immunoglobulin.
- chimeric antibody refers to an antibody in which at least one of the antibody chains (heavy or light) comprises variable region sequences from one species (e.g., mouse) and constant region sequences from another species (e.g., human).
- the term “chimeric antibody” is intended to encompass antibodies in which: (i) the heavy chain is chimeric but the light chain comprises variable and constant regions from only one species; (ii) the light chain is chimeric but the heavy chain comprises variable and constant regions from only one species; and (iii) both the heavy chain and the light chain are chimeric.
- the monoclonal antibody or the antibody fragment may be of non-human mammal origins. Examples for such antibodies are mouse, rat, rabbit, goat, mouse, rat, rabbit, goat, ape, and monkey antibodies. In one particular embodiment, the antibody or the antibody fragment is a mouse antibody or antibody fragment.
- the polyclonal antibody or the monoclonal antibody or the antibody fragment according to any one of the above embodiments has an IgG, IgA, IgD, IgE or IgM structure.
- the antibody or the antibody fragment, e.g. monoclonal antibody or the antibody fragment has an IgG structure.
- the antibody or the fragment thereof, and in particular a polyclonal antibody or a fragment thereof is specific to Zika virus.
- the antibody or the fragment thereof is specific to Dengue virus.
- the antibody or the fragment is selected from the antibody or the fragment specific to a virus selected from Yellow fever virus, Japanese encephalitis virus, West Nile encephalitis virus, Usutu encephalitis virus, and Bagaza encephalitis virus.
- the antibodies are human or humanized antibodies.
- the antibodies are IgG antibodies.
- the treatment is a passive immunization of the mammal fetus.
- the fetus is a fetus infected by a virus of Flavivirus genus.
- the fetus is infected by Zika virus.
- the fetus is infected by a virus causing to a disease selected from Yellow fever, Dengue fever, Japanese encephalitis, West Nile encephalitis, Kyasanur Forest disease, Murray Valley encephalitis, St. Louis encephalitis, Tick-borne encephalitis, and Omsk hemorrhagic fever.
- said viral infection correlates with an increase in cell death in an animal or in a human infected by said virus.
- the infection and in particular viral infection is correlated with inhibiting fetus brain development.
- the fetus is a healthy fetus.
- the treatment is prophylactic or preventive treatment.
- the treatment is a prophylactic immunization.
- the mammal fetus is human or non-human fetus.
- the fetus is human fetus.
- the fetus is non-human mammal fetus.
- the non-human fetus is an fetus of livestock animals such as cattle, pigs, sheep, goats, horses, mules, asses, buffalo, or camels.
- the fetus is cattle fetus.
- the domestic pet fetus is a cat or dog fetus
- the rodent fetus is a fetus of a mouse, rat, guinea pig or hamster
- the lagomorpha fetus is a rabbit fetus
- the primate fetus is monkey such as macaques or ape fetus such as chimpanzee.
- the pharmaceutical composition further comprises pharmaceutically acceptable excipients.
- compositions may contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
- the pharmaceutical composition according to the present invention is formulated as an extended release formulation.
- extended release refers to a mode of releasing an active agent from the formulation such that it is available to an organism over a period of time .
- An extended release formulation of an active agent may be accomplished, e.g., by embedding the active agent in a web of substance that dissolves slowly, such that the active ingredient slowly and regularly leeches from the coating, or by swelling up the active agent to form a gel with a nearly impenetrable surface, wherein the drug slowly exits the semipermeable layer.
- the active compound is anti -viral compound.
- such anti-viral compound is selected from nucleoside or nucleotide reverse- transcriptase inhibitors such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir disoproxil fumarate and emtricitabine; non-nucleoside reverse -transcriptase inhibitors such as nevirapine, efavirenz, delavirdine; protease inhibitors such as saquinavir, indinavir, ritonavir, nelfnavir, amprenavir, lopinavir, ritonavir, atazanavir, fosamprenavir, tipranavir, darunavir; and virus entry inhibitors e.g. enfuvirtide or maraviroc.
- the active compound is anti-fungi compound.
- said compound is selected from polyene, azole, allylamine and morpholine anti-fungi compound.
- the anti-fungi compound is selected from fluconazole, itraconazole, or posaconazole.
- the active compound is a non-teratogenic compound, e.g. belonging to FDA Pregnancy Categories A, B, C, D or N.
- the intrauterine administering or administration is selected from the group consisting of intra-amniotic administration, intraumbilical cord administration, intra-placental vasculature administration, intrafetus administration and administration by a vaginal guided procedure.
- the administration is intra-amniotic sac.
- the administration is performed during amniocentesis .
- the administration is via amniotic sac puncture and/or injection.
- the administration is intraumbical cord administration.
- intraumbilical cord administration comprises administration into umbilical vein and/or into umbilical artery.
- intra-placental vasculature administration comprises administration into placental vein and/or artery. It is speculated without being limited to any particular theory that administration of an active agent, and in particular of antibody to umbilical and/or placental vein results in concentrating the active compound and its activity in the fetus, when administering to the umbilical and/or placental artery results in concentrating the active compound and its activity in the fetal side of the placenta.
- the active compound, and in particular antibody or antibody fragment as described above are administered directly to the fetus. In one embodiment, the administration is intra-muscular administration to the fetus.
- the administration comprises using a guidance such as ultrasound guidance, guidance using an optical fiber or injectable guide.
- a guidance such as ultrasound guidance, guidance using an optical fiber or injectable guide.
- the administration comprises use of an optical fiber or ultrasound guidance.
- the administration comprises use of optical and injectable guide.
- the administration comprises using any combination of ultrasound, optical and injectable guidance. In other embodiment, no guidance is used at all.
- the administration may be a single administration or multiple administration.
- the administration is performed via a pump.
- the present invention provides a pharmaceutical composition comprising an effective amount of non-maternal antibodies or fragment thereof, for use in treating human fetus, wherein said antibodies or fragment thereof are capable of binding to a virus of Flavivirus genus and said pharmaceutical composition is administered via intrauterine administration.
- the intrauterinal administration is selected from intra-amniotic administration, intraumbilical cord administration, intra-placental vasculature administration, intrafetus administration and administration by vaginal procedure.
- the virus is selected from Zika virus, Dengue virus, Yellow fever virus, Japanese encephalitis virus, West Nile encephalitis virus, Usutu encephalitis virus, and Bagaza encephalitis virus.
- the antibody or fragment thereof are human, humanized or chimeric antibodies.
- the fetus is a healthy fetus.
- the fetus is infected by Zika virus.
- the antibodies are polyclonal antibodies.
- the present invention provides a pharmaceutical composition comprising an effective amount of non-maternal antibodies or fragment thereof, for use in treating human fetus, wherein said antibodies or fragment thereof are capable of binding to Zika virus and said pharmaceutical composition is administered via intrauterine administration.
- the intrauterinal administration is selected from intra-amniotic administration, intraumbilical cord administration, intra-placental vasculature administration, intrafetus administration and administration by vaginal procedure.
- the antibodies are polyclonal antibodies.
- the antibody or fragment thereof are human, humanized or chimeric antibodies.
- the fetus is a healthy fetus.
- the fetus is infected by Zika virus.
- the present invention provides a pharmaceutical composition comprising an effective amount of non-maternal antibodies or fragment thereof, for use in treating a healthy human fetus, wherein said antibodies or fragment thereof are selected from polyclonal or monoclonal selected from humanized, chimeric or human antibodies or fragment thereof capable of binding to Zika virus and said pharmaceutical composition is administered via intrauterine administration selected from intra-amniotic administration, intraumbilical cord administration, intra- placental vasculature administration, intrafetus administration and administration by vaginal procedure.
- the present invention provides a method for treatment of a disease caused by a virus of Flavivirus genus in a mammal fetus comprising administering intrauterinally a pharmaceutical composition comprising an effective amount of an active compound capable of treating the disease.
- the virus is selected from the group consisting of Zika virus, Dengue virus, Yellow fever virus, Japanese encephalitis virus, West Nile encephalitis virus, Usutu encephalitis virus, and Bagaza encephalitis virus.
- the active agent is antibody or fragment thereof that binds specifically to the virus of Flavivirus genus.
- the antibody is a non- maternal antibody or a fragment thereof.
- the antibody is a polyclonal antibody or a fragment thereof.
- the antibody or a fragment thereof is a human antibody or the fragment thereof.
- the antibody is a monoclonal antibody or a fragment thereof.
- the antibody or the fragment thereof, and in particular a polyclonal antibody or a fragment thereof is specific to Zika virus.
- the antibody or the fragment thereof is specific to Dengue virus.
- the antibody or the fragment is specific to a virus selected from Yellow fever virus, Japanese encephalitis virus, West Nile encephalitis virus, Usutu encephalitis virus, and Bagaza encephalitis virus.
- the antibodies are IgG antibodies.
- the treatment is a passive immunization of the mammal fetus.
- the intrauterine administering or administration is selected from the group consisting of intra-amniotic administration, intraumbilical cord administration, intra-placental vasculature administration, intrafetus administration and administration by a vaginal guided procedure.
- the administration is intra-amniotic sac.
- Devices in particular intrauterine devices, allowing intrauterine administration may be particularly useful .
- the fetus is a human fetus.
- the fetus is non-human mammal fetus.
- the fetus is a healthy fetus and the treatment is a prophylactic immunization.
- the fetus is infected by a virus of Flavivirus genus, and in particular infected by Zika virus.
- the active agent is a small molecule capable of treating a virus of Flavivirus genus.
- the term “comprising” includes the meaning of “consisting” and may be substituted by it.
- the study aims to evaluate 3 separate, but related, methodologies for intrauterine delivery of anti -Candida antibodies: (a) injection of antibodies into the umbilical vein, (b) direct injection of antibodies into amniotic fluid; and (c) fetal intramuscular injection of antibodies.
- Treatment group Six (6) sheep are included in each treatment group comprising a total of 18 sheep. Each methodology of antibody administration is conducted at 3 separate time points during gestation paralleling first, second and third trimester equivalents in sheep gestation (week 5, 10, and 15 respectively).
- Control group A control group comprises nine (9) sheep divided into three subgroups which undergo sham amniocentesis procedures, at the same time points of gestation, in which saline is administered instead of the experimental drug.
- Access to the fetal venous circulation is obtained through cordocentesis.
- a needle is placed under visual guidance into the umbilical vein.
- access may be gained to other components of the placental vasculature.
- Venous access is confirmed via aspiration of fetal blood (samples are saved for laboratory testing) and injection of fluid resulted in visible turbulence in the vein (flowing towards the fetus or in the placental bed) or arterial access can be confirmed by flow towards the placenta, confirming needle position.
- the study drug or saline is then administered according to study group.
- the right or left hind quarter is identified and subsequently a site for IM injection in the left or right anterolateral thigh.
- Access to the amniotic sac is achieved and confirmed via aspiration of amniotic fluid (samples are saved for laboratory testing).
- a needle is placed under ultrasound guidance into the injection site in the musculature. After the location is confirmed, study drug or saline is then be administered according to study group.
- Intragestational Ultrasound Periodic ultrasound examinations are performed to assess the viability and health of the pregnancy both before and the after study.
- the study aims to produce human plasma-derived Anti-Zika IgG for microinjection to Zika pregnant mice embryo amniotic cavity and to evaluate the safety and efficacy of intrauterine administration of anti-Zika antibodies that are absorbed by the fetus.
- the study aims to provide a medical countermeasure against maternal-fetal transmission, infection and disease caused by the Zika virus.
- the plasma-derived IgG are superior to mAbs due to the broader spectrum of epitopes that are available from plasma pools of heterogeneous human donors.
- the plasma-derived IgG is the best solution as a preventative of abnormal brain development in newborns and fetus of a post-exposure pregnant woman.
- Plasma units from convalescent donors are pooled and IgG are purified using Protein G chromatography to obtain an hyperimmune -IgGs laboratory scale batch.
- the plasma pool titer are determined using a quantitative Cellular assay (Plaque Reduction Neutralization Test, PRNT), Plasma are aliquoted, and kept frozen for use and establishment of the therapeutic dose.
- PRNT Protein Reduction Neutralization Test
- mice were treated with (or A 129) mice.
- mice Two mouse models of Zika disease were recently characterized which are susceptible to lethal and nonlethal Zika virus infection.
- the models are immunocompromised mice lacking the receptor for type I interferon (IFN ⁇ / ⁇ ) on a C57BL/6 background (Ifnarl -/- mice, Lazear et al., 2016, Cell Host & Microbe, May 11; 19(5):720-30), or on 129 background (A129, Sapparapu et al., 2016, Nature. Dec 15; 540(7633):443-447). Ifnarl -/- mice strains (alternatively A129 mice) are used to determine the therapeutic dose that will protect from the Zika virus (ZIKV) effect.
- ZIKV Zika virus
- mice Three groups of eight young mice each are infected with 1 ⁇ 10 3 PFU/mouse by the subcutaneous route (SC) in the footpad.
- SC subcutaneous route
- An additional mock infected control group of 4 mice are given PBS by the same route.
- PI post infection
- Anti-Zika IgG are administered at low and high doses (Groups A and B, respectively) via an intraperitoneal or IV route.
- Additional group are injected with non-specific antibodies, as control. Mice are monitored three times each day for clinical signs of disease as described in Table 1.
- Weights are recorded daily. These mice begin to lose weight at day 5 post infection (PI), at day 7 PI they lose between 15-25% of their starting weight. Hindlimb weakness is observed in most at d6 PI, and partial to complete paralysis at d7 PI. A set of humane clinical end points are a 20% weight loss, or 10% weight loss and a clinical symptom, which mandated euthanasia, as are determined by the veterinary stuff.
- mice are sacrificed, and a group of four animals from each group are undergoing necropsy. Samples of spleen, liver, brain and ovary are collected and immediately frozen at -80°C for virological analysis or inserted into pots containing 10% neutral buffered saline for microscopic analysis. Blood is collected into RNAprotect tubes (Qiagen, UK) for viral load testing.
- Prophylactic study Two groups of 10 Ifnar 1 -/- female mice each (groups A and B), and a control group (C) of 5 Ifnar 1 -/- female mice, are mate with WT B57BL/6 males. Pregnant females (estimated 8/group) are continuing with the study. At embryonic day E5.5 pregnant mice in group A are treated with the therapeutic dose of Anti-Zika IgG (that was determined in the previous study). Pregnant mice in group B are treated with non-specific antibodies as a control. At E6.5 all mice are infected with 1 ⁇ 10 3 PFU/mouse by SC injection in the footpad. An additional mock infected mice control group (group C) is given PBS by the same route.
- Treatment includes administration of Anti-Zika IgG by intrauterine administration and IV administration and newborns are evaluated immediately after birth for intrauterine growth restriction, ZIKV infection and injury of the fetal brain Example 3. Uses of Anti-Zika hyperimmune IgG for preclinical studies in a pig model
- Pregnant pigs are infected with ZIKV post treatment with Anti-Zika IgG, and newborns are evaluated immediately after birth (newborns size, ZIKA infection and damage to the brain).
- Prophylactic study 1 Two groups of 3 females each (groups A and B), and a control group (C) of 3 females, are mate with males. During the 1 st trimester (about 5 weeks), pregnant pigs in group A are treated with the therapeutic dose of Anti-Zika IgG. Pregnant pigs in group B are treated with non-specific antibodies as a control. After one day all females are infected with Zika virus inoculation by SC injection in the footpad/back. An additional mock infected control group (group C) is given PBS by the same route.
- Treatment includes administration of Anti-Zika IgG to the fetus through the umbilical cord vein, and newborns are evaluated immediately after birth for intrauterine growth restriction, ZIKV infection and injury of the fetal brain
- Prophylactic study 2 As above, where the treatment includes administration of Anti-Zika IgG to the amniotic sac.
- Prophylactic study 3 As above, where the treatment includes administration of Anti-Zika IgG to the fetus by intra muscular injection to the fetus through the amniotic sac.
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GIOVANNI NIGRO ET AL.: "Passive immunization during pregnancy for congenital cytomegalovirus infection", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 353, no. 13, 31 December 2005 (2005-12-31), pages 1350 - 1362, XP055414466 * |
SAPPARAPU GOPAL ET AL.: "Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice", NATURE, vol. 540, no. 7633, 15 December 2016 (2016-12-15), pages 443 - 447, XP055412748 * |
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WO2019244130A1 (en) * | 2018-06-21 | 2019-12-26 | Emergent Biosolutions Canada Inc. | Zika neutralizing antibody compositions and methods of using the same |
US20210147514A1 (en) * | 2018-06-21 | 2021-05-20 | Emergent Biosolutions Canada Inc. | Zika neutralizing antibody compositions and methods of using the same |
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