WO2021093639A1 - 抗水痘-带状疱疹病毒的抗体 - Google Patents

抗水痘-带状疱疹病毒的抗体 Download PDF

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WO2021093639A1
WO2021093639A1 PCT/CN2020/126159 CN2020126159W WO2021093639A1 WO 2021093639 A1 WO2021093639 A1 WO 2021093639A1 CN 2020126159 W CN2020126159 W CN 2020126159W WO 2021093639 A1 WO2021093639 A1 WO 2021093639A1
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vzv
antibody
antigen
variable region
chain variable
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English (en)
French (fr)
Chinese (zh)
Inventor
廖化新
王月明
郑伟宏
李嘉祺
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Zhuhai Trinomab Biotechnology Co Ltd
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Zhuhai Trinomab Biotechnology Co Ltd
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Priority to US17/775,727 priority Critical patent/US12491386B2/en
Priority to EP20887206.9A priority patent/EP4063383A4/en
Priority to PH1/2022/551151A priority patent/PH12022551151A1/en
Priority to JP2022526794A priority patent/JP7689955B2/ja
Publication of WO2021093639A1 publication Critical patent/WO2021093639A1/zh
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—DNA viruses
    • C07K16/085—Orthoherpesviridae (F), e.g. pseudorabies virus or Epstein-Barr virus
    • C07K16/088—Varicella-zoster virus
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • G01N33/56994—Herpetoviridae, e.g. cytomegalovirus, Epstein-Barr virus
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies
    • 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
    • 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
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/01—DNA viruses
    • G01N2333/03—Herpetoviridae, e.g. pseudorabies virus
    • G01N2333/04—Varicella-zoster virus
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2469/00—Immunoassays for the detection of microorganisms
    • G01N2469/20—Detection of antibodies in sample from host which are directed against antigens from microorganisms

Definitions

  • VZV Varicella-zoster virus
  • the envelope of VZV contains a variety of glycoproteins, such as gE, gB, gH, gI, gC, and gL.
  • VZV glycoprotein not only involves the entry of viruses into cells, but also transfers from infected cells to uninfected cells, which can stimulate humoral and cellular immune responses to the virus.
  • VZV enters the body through the conjunctiva and respiratory mucosa when it is first infected and causes chickenpox, that is, the primary infection of varicella (varicella), which is a highly contagious common disease in children.
  • chickenpox is a self-limiting disease with a duration of about 4 to 5 days; for children with immunodeficiency and non-immune newborns, infection with chickenpox may cause serious complications, such as viral pneumonia , Encephalitis, etc., can even lead to fatal consequences.
  • a small number of adults will be infected with chickenpox with severe symptoms, often complicated by pneumonia (20%-30%), and a high mortality rate.
  • VZV can also be latent in the ganglion. Factors such as old age, weakened immune system or immunosuppression due to diseases or drugs will cause the latent virus to be reactivated, causing herpes zoster distributed along the nerve, that is, recurrent herpes zoster infection ( zoster). Recurrent infection with VZV can cause abnormal disseminated infection of skin lesions and damage to organs such as lung, brain, liver, kidney, heart, and eyes. It is often accompanied by postherpetic neuralgia, and even death in severe cases. The postherpetic neuralgia pain is severe and can last for several years, which greatly affects the patient's quality of life. The incidence of herpes zoster and postherpetic neuralgia increases with age, which causes a greater social burden on an aging society.
  • VZV virus infection the most important preventive measure for VZV virus infection is vaccination.
  • varicella vaccine and herpes zoster vaccine are currently on the market for prevention.
  • Other treatments are based on antiviral drugs, including the use of acyclovir, famciclovir, valacyclovir, acyclovir, and arabinosine. Therefore, there is currently no effective and specific treatment.
  • VZIG varicella-zoster immunoglobulin
  • the U.S. FDA has approved a varicella-zoster immunoglobulin (VZIG), produced by Canada Cangene, for use in high-risk groups of VZV infection, mainly pregnant women and newborns .
  • VZIG varicella-zoster immunoglobulin
  • the VZV immunoglobulin is a blood product, which has resource scarcity and batch-to-batch variability, and there is a window period, and there is a risk of spreading pathogens.
  • this type of product has the safety problem of spreading blood-borne pathogens such as AIDS virus, hepatitis B virus, hepatitis C virus, etc., so there are defects in application.
  • the existing vaccines and systemic antiviral drugs can prevent and control VZV infection, they cannot eliminate many complications of VZV infection. Therefore, there is still a need to find effective neutralizing antibodies against VZV, which can effectively detect VZV and block VZV from infecting hosts and spreading between hosts. In addition, there is still a need for improved treatment methods for VZV infection, especially methods suitable for emergency intervention against VZV infection.
  • the anti-VZV antibodies and their compositions provided in this application meet the above-mentioned needs.
  • the present invention provides a new neutralizing anti-VZV antibody capable of binding to VZV with high affinity, a composition containing the antibody, a kit, the use of the anti-VZV antibody, and a method for use and preparation thereof.
  • the present invention provides isolated anti-VZV antibodies and antigen fragments thereof.
  • the anti-VZV antibody and antigen fragments thereof comprise one, two or three CDRs (preferably three CDRs) selected from the sequence of the VH region of any antibody shown in Table 1.
  • the antibody of the present invention comprises one, two or three CDRs (preferably three CDRs) selected from the VL region sequence of any antibody shown in Table 1.
  • the antibody of the present invention comprises the 6 CDR region sequences of any one of the antibodies shown in Table 1.
  • the CDR sequence of the antibody is the CDR sequence shown in Table II.
  • the anti-VZV antibody or antigen-binding fragment thereof of the present invention comprises A) the complementarity determining region (CDR) of the heavy chain: (i) CDR1, which comprises an amino acid selected from SEQ ID NO: 1, 7 and 13 A sequence, or a sequence containing one or more and no more than 5 amino acid substitutions (such as conservative substitutions), deletions, or insertions relative to the sequence, (ii) CDR2, which includes SEQ ID NO: 2, The amino acid sequence of 8 and 14, or a sequence containing one or more and no more than 5 amino acid substitutions (such as conservative substitutions), deletions or insertions relative to the sequence, (iii) CDR3, which comprises a sequence selected from SEQ ID NO: the amino acid sequence of 3, 9 and 15, or the sequence containing one or more and no more than 5 amino acid substitutions (such as conservative substitutions), deletions or insertions relative to the sequence, and B) The complementarity determining region (CDR) of the light chain: (i) CDR1, which comprises an amino acid selected
  • a sequence of amino acid substitutions (such as conservative substitutions), deletions or insertions of more than 5 amino acids, (iii) CDR3, which comprises an amino acid sequence selected from SEQ ID NO: 6, 12, and 18, or is relative to the sequence
  • the anti-VZV antibody or antigen-binding fragment thereof of the present invention comprises A) the complementarity determining region (CDR) of the heavy chain: (i) CDR1, which consists of the amino acid sequence of SEQ ID NO: 1, (ii) CDR2, which consists of the amino acid sequence of SEQ ID NO: 2, (iii) CDR3, which consists of the amino acid sequence of SEQ ID NO: 3, and B) the complementarity determining region (CDR) of the light chain: (i) CDR1, which It consists of the amino acid sequence of SEQ ID NO: 4, (ii) CDR2, which consists of the amino acid sequence of SEQ ID NO: 5, and (iii) CDR3, which consists of the amino acid sequence of SEQ ID NO: 6.
  • CDR complementarity determining region
  • the anti-VZV antibody or antigen-binding fragment thereof of the present invention comprises A) the complementarity determining region (CDR) of the heavy chain: (i) CDR1, which consists of the amino acid sequence of SEQ ID NO: 7, (ii) CDR2, which consists of the amino acid sequence of SEQ ID NO: 8, (iii) CDR3, which consists of the amino acid sequence of SEQ ID NO: 9, and B) the complementarity determining region (CDR) of the light chain: (i) CDR1, which It consists of the amino acid sequence of SEQ ID NO: 10, (ii) CDR2, which consists of the amino acid sequence of SEQ ID NO: 11, and (iii) CDR3, which consists of the amino acid sequence of SEQ ID NO: 12.
  • the anti-VZV antibody or antigen-binding fragment thereof of the present invention comprises A) the complementarity determining region (CDR) of the heavy chain: (i) CDR1, which consists of the amino acid sequence of SEQ ID NO: 13, (ii) CDR2, which consists of the amino acid sequence of SEQ ID NO: 14, (iii) CDR3, which consists of the amino acid sequence of SEQ ID NO: 15, and B) the complementarity determining region (CDR) of the light chain: (i) CDR1, which It consists of the amino acid sequence of SEQ ID NO: 16, (ii) CDR2, which consists of the amino acid sequence of SEQ ID NO: 17, and (iii) CDR3, which consists of the amino acid sequence of SEQ ID NO: 18.
  • CDR complementarity determining region
  • the anti-VZV antibody or antigen-binding fragment thereof of the present invention comprises a heavy chain variable region VH, which comprises an amino acid sequence selected from SEQ ID NO: 19, 21, 23 or 25 that has at least 75%, 76 %, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, An amino acid sequence of 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity or higher identity or consists of the sequence, and the anti-VZV antibody comprising the VH has the ability to bind to VZV .
  • the anti-VZV antibody or antigen-binding fragment thereof of the present invention comprises a heavy chain variable region VH, which comprises the 6 CDRs of any antibody shown in Table II, and is selected from SEQ ID NO: 19, 21
  • the amino acid sequence of, 23 or 25 has at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity, and the anti-VZV antibody containing the VH has the ability to bind to VZV.
  • the heavy chain variable region VH of the anti-VZV antibody contains one or more substitutions (such as conservative substitutions), inserts, and the amino acid sequence selected from SEQ ID NO: 19, 21, 23, or 25. Or the missing amino acid sequence, the anti-VZV antibody containing the VH has the ability to bind to VZV.
  • the anti-VZV antibody or antigen-binding fragment thereof of the present invention comprises a light chain variable region VL, which comprises an amino acid sequence selected from SEQ ID NO: 20, 22, 24 or 26 that has at least 75%, 76% %, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, An amino acid sequence of 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity or higher identity or consists of the sequence, and the anti-VZV antibody comprising the VL has the ability to bind to VZV .
  • the anti-VZV antibody or antigen-binding fragment thereof of the present invention comprises a light chain variable region VL, which comprises 6 CDRs of any antibody shown in Table II, and is selected from SEQ ID NO: 20, 22
  • the amino acid sequence of, 24 or 26 has at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity, and the anti-VZV antibody containing the VL has the ability to bind to VZV.
  • the light chain variable region VL of the anti-VZV antibody contains one or more substitutions (e.g. conservative substitutions), inserts, and an amino acid sequence selected from SEQ ID NO: 20, 22, 24, or 26. Or the missing amino acid sequence, the anti-VZV antibody containing the VH has the ability to bind to VZV.
  • the anti-VZV antibody or antigen-binding fragment thereof of the present invention comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:
  • the VH of the heavy chain variable region contains at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82% of the amino acid sequence selected from SEQ ID NO: 19, 21, 23 or 25 %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or An amino acid sequence with 99% identity or higher identity or consists of the sequence;
  • the light chain variable region VL contains an amino acid sequence selected from SEQ ID NO: 20, 22, 24 or 26 that has at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% , 93%, 94%, 95%, 96%, 97%, 98% or 99% identity or higher identity amino acid sequence or consists of said sequence, or
  • the VH of the heavy chain variable region contains the 6 CDRs of any antibody shown in Table II, and has at least 75%, 76%, 77%, and an amino acid sequence selected from SEQ ID NO: 19, 21, 23, or 25. 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% , 95%, 96%, 97%, 98%, or 99% identity;
  • the light chain variable region VL contains the 6 CDRs of any antibody shown in Table II, and is selected from SEQ ID NO: 20, 22, 24 Or the amino acid sequence of 26 has at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89 %, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity, the anti-VZV antibody comprising the
  • the VH of the heavy chain variable region comprises an amino acid sequence with one or more substitutions (such as conservative substitutions), insertions or deletions compared with the amino acid sequence selected from SEQ ID NO: 19, 21, 23 or 25; light chain
  • the variable region VL comprises an amino acid sequence having one or more substitutions (such as conservative substitutions), insertions or deletions compared with an amino acid sequence selected from SEQ ID NO: 20, 22, 24, or 26, including the VH and VL
  • the anti-VZV antibody has the ability to bind to VZV.
  • the present invention provides an anti-VZV antibody or antigen-binding fragment thereof, wherein the heavy chain variable region VH comprises or consists of the amino acid sequence shown in SEQ ID NO: 19; the light chain variable region VL comprises SEQ The amino acid sequence shown in ID NO:20 or consists of it.
  • the present invention provides an anti-VZV antibody or antigen-binding fragment thereof, wherein the heavy chain variable region VH comprises or consists of the amino acid sequence shown in SEQ ID NO: 21; the light chain variable region VL comprises SEQ The amino acid sequence shown in ID NO: 22 or consists of it.
  • the present invention provides an anti-VZV antibody or antigen-binding fragment thereof, wherein the heavy chain variable region VH comprises or consists of the amino acid sequence shown in SEQ ID NO: 23; the light chain variable region VL comprises SEQ The amino acid sequence shown in ID NO: 24 or consists of it.
  • the present invention provides an anti-VZV antibody or antigen-binding fragment thereof, wherein the heavy chain variable region VH comprises or consists of the amino acid sequence shown in SEQ ID NO: 25; the light chain variable region VL comprises SEQ The amino acid sequence shown in ID NO: 26 or consists of it.
  • the aforementioned anti-VZV antibody or antigen-binding fragment thereof further comprises a heavy chain and/or light chain constant region sequence derived from a human antibody germline consensus sequence.
  • the antibodies of the present invention also encompass antibodies that compete with any of the antibodies described above for binding to VZV, and antibodies that bind to the same epitope of VZV as any of the antibodies described above.
  • the anti-VZV antibody of the present invention also encompasses antibody fragments thereof, preferably antibody fragments selected from the group consisting of Fab, Fab'-SH, Fv, scFv or (Fab') 2 fragments.
  • the anti-VZV antibody of the present invention is a neutralizing antibody for use in neutralizing VZV.
  • the invention provides a nucleic acid encoding any of the above anti-VZV antibodies or fragments thereof.
  • a vector comprising the nucleic acid is provided.
  • the vector is an expression vector.
  • a host cell comprising the vector is provided.
  • the host cell is eukaryotic.
  • the host cell is selected from mammalian cells or other cells suitable for preparing antibodies or antigen-binding fragments thereof.
  • the host cell is prokaryotic.
  • the present invention provides a method for preparing an anti-VZV antibody or antigen-binding fragment thereof, wherein the method comprises culturing the host cell under conditions suitable for expressing a nucleic acid encoding the antibody or antigen-binding fragment thereof, And optionally isolating the antibody or antigen-binding fragment thereof. In a certain embodiment, the method further comprises recovering the anti-VZV antibody or antigen-binding fragment thereof from the host cell.
  • the present invention provides an anti-VZV antibody or antigen-binding fragment thereof prepared by the method of the present invention.
  • the present invention provides a composition comprising any anti-VZV antibody or antigen-binding fragment thereof described herein, preferably the composition is a pharmaceutical composition.
  • the composition further comprises a pharmaceutical carrier.
  • the anti-VZV antibodies and antigen-binding fragments thereof contained in the composition are coupled to the coupling portion.
  • the present invention provides that the anti-VZV antibody and the antigen-binding fragment thereof contained in the composition capable of extending the half-life of the antibody or the antigen-binding fragment thereof are coupled to the coupling portion.
  • composition comprising any anti-VZV antibody or fragment thereof.
  • the composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent.
  • the composition is a pharmaceutical composition.
  • the present invention relates to a method of neutralizing VZV in a subject or sample, the method comprising: (a) contacting the subject or sample with any anti-VZV antibody or fragment thereof described herein; and (b) detecting the anti-VZV antibody Or the formation of a complex between its fragments and VZV.
  • the anti-VZV antibody and antigen-binding fragment thereof of the present invention further include a detectable label.
  • the present invention also relates to the use of any anti-VZV antibody or fragment thereof herein in the preparation of a composition or medicine or kit for neutralizing VZV of a subject.
  • the present invention relates to a method of preventing and treating a subject's VZV infection or one or more diseases or symptoms associated with VZV infection (such as chickenpox, shingles), the method comprising administering to the subject An effective amount of any anti-VZV antibody or fragment thereof herein, or administration of the pharmaceutical composition of the present invention.
  • the subject is a newborn baby, a premature baby, a woman in childbirth, and an organ transplant operation, hematological malignancy, malignant tumor, nephrotic syndrome, etc. receiving immunosuppressive agents, cytotoxic drugs or radiotherapy, etc. Those who cause immune insufficiency.
  • the present invention also relates to the use of any anti-VZV antibody or fragment thereof herein in the preparation of a medicament for the treatment or prevention of VZV infection or one or more diseases or symptoms related to VZV infection.
  • the condition associated with VZV is chickenpox or shingles.
  • the present invention relates to a method of increasing, enhancing, or stimulating an immune response or function in a subject, the method comprising administering to the subject an effective amount of any anti-VZV antibody or fragment thereof herein, thereby The subject improves, enhances, or stimulates the immune response or function.
  • any anti-VZV antibody or fragment thereof herein is for use as a medicine.
  • the present invention provides a method for diagnosing whether a subject is infected with VZV, which includes using the anti-VZV antibody and antigen-binding fragment thereof of the present invention to detect the presence and/or level of VZV in a sample from the subject.
  • the anti-VZV antibody and antigen-binding fragment thereof of the present invention further include a detectable label.
  • the present invention provides a kit containing the antibody or composition of the present invention, such as a diagnostic kit, a detection kit, a treatment kit and the like.
  • the invention also encompasses any combination of any of the embodiments described herein. Any embodiment described herein or any combination thereof is applicable to any and all anti-VZV antibodies or fragments thereof, methods and uses of the invention described herein.
  • the present invention provides fully human antibodies and antigen-binding fragments thereof capable of specifically recognizing/binding VZV.
  • the fully human antibodies and antigen-binding fragments thereof are neutralizing antibodies that have a neutralizing effect and can inhibit VZV infection, and
  • the antibody and its antigen-binding fragments have good affinity, strong specificity, no heterologous serum reaction, and no risk of spreading other infectious diseases, and can be used to prevent and treat VZV infection in subjects or one or one related to the infection Various diseases or symptoms, such as chickenpox, shingles.
  • Figure 1 SDS-PAGE test results of the purified antibody. Lanes 1, 4 and 7 are non-reduced fully human VZV monoclonal antibodies TRN1024, TRN1025 and TRN1026, respectively. Lanes 3, 6, and 9 are non-reduced fully human VZV. Monoclonal antibodies TRN1024, TRN1025 and TRN1026, lanes 2, 5, and 8 are Mark proteins.
  • FIG. 2 ELISA test results of three fully human VZV monoclonal antibodies TRN1024, TRN1025, and TRN1026.
  • Figure 3 Fitted association and dissociation sensorgrams of three fully human VZV monoclonal antibodies TRN1024, TRN1025, and TRN1026.
  • FIG. 4 Anti-nuclear resistance test results of three fully human VZV monoclonal antibodies TRN1024, TRN1025, and TRN1026.
  • the term “comprising” or “including” means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps.
  • the term “comprises” or “includes” when used, unless otherwise specified, it also covers the case consisting of the stated elements, integers or steps.
  • an antibody variable region that "comprises” a specific sequence when referring to an antibody variable region that "comprises” a specific sequence, it is also intended to encompass the antibody variable region composed of the specific sequence.
  • antibody is used in the broadest sense herein and encompasses a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they It suffices to show the desired antigen-binding activity.
  • Intact antibodies will generally contain at least two full-length heavy chains and two full-length light chains, but may include fewer chains in some cases, for example, antibodies naturally occurring in camels may contain only heavy chains.
  • monoclonal antibody refers to a single copy or cloned antibody derived, for example, from eukaryotes, prokaryotes or phage clones, ie, except for possible variant antibodies that are usually present in very small amounts (For example, a variant antibody that contains a natural mutation or is produced during the production of a monoclonal antibody product), each antibody constituting the population is the same and/or binds the same epitope.
  • the modifier “monoclonal” refers to the characteristics of an antibody obtained from a substantially homogeneous antibody population, and should not be construed as requiring the production of the antibody by any specific method.
  • Monoclonal antibodies can be produced, for example, by hybridoma technology, recombinant technology, phage display technology, synthetic technology such as CDR grafting, or a combination of such or other techniques known in the art.
  • whole antibody includes at least two heavy chains (H) and two light chains (L).
  • Each heavy chain is composed of a heavy chain variable region (abbreviated as VH herein) and a heavy chain constant region from N to C terminal.
  • the heavy chain constant region is composed of three structural domains CH1, CH2 and CH3.
  • Each light chain is composed of a light chain variable region (abbreviated as VL herein) and a light chain constant region.
  • the light chain constant region consists of a domain CL.
  • the VH and VL regions can be further divided into complementarity determining regions (CDR) and intervening framework regions (FR).
  • CDR complementarity determining regions
  • FR intervening framework regions
  • Each VH and VL consists of three CDRs and 4 FRs, arranged in the following order from the amino terminal to the carboxy terminal: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • “Native antibodies” refer to naturally occurring immunoglobulin molecules with different structures.
  • the "native sequence Fc domain” contains the same amino acid sequence as the amino acid sequence of the Fc domain found in nature.
  • the natural sequence human Fc domain includes, for example, the natural sequence human IgG1 Fc domain (non-A and A allotypes); the natural sequence human IgG2 Fc domain; the natural sequence human IgG3 Fc domain; and the natural sequence human IgG4 Fc domain; and its naturally occurring Variants.
  • Human antibody refers to an antibody having an amino acid sequence that corresponds to the amino acid sequence of an antibody produced by human or human cells or derived from a non-human source, which utilizes a human antibody library or other human antibodies Coding sequence. This definition of human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.
  • neutralizing antibody refers to an antibody or antibody fragment capable of binding to a pathogen and eliminating or significantly reducing the pathogen's virulence (for example, the ability to infect cells). Such neutralizing antibodies usually play a role in killing cells, preventing pathogens from invading cells.
  • the invention encompasses fragments of anti-VZV antibodies.
  • antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab') 2 , diabodies, linear antibodies, single-chain antibody molecules (such as scFv); and multispecific antibody fragments formed Sex antibody.
  • Papain digestion of the antibody produces two identical antigen-binding fragments, called "Fab” fragments, each with a single antigen-binding site, and the remaining "Fc” fragment, whose name reflects its ability to be easily crystallized.
  • Pepsin treatment produces F(ab') 2 fragments that have two antigen binding sites and are still capable of cross-linking antigens.
  • CDR region or “CDR” or “hypervariable region” is an amino acid region in the variable region of an antibody that is mainly responsible for binding to an epitope.
  • the CDRs of the heavy and light chains are usually called CDR1, CDR2, and CDR3, and are numbered sequentially from the N-terminus.
  • CDR complementarity determining region
  • the CDR of the antibody of the present invention is a CDR sequence located at the following Kabat residue positions according to the Kabat numbering system:
  • the CDR can also be determined based on having the same Kabat numbering position as a reference CDR sequence (for example, any of the exemplary CDRs of the present invention).
  • variants in relation to antibodies refers herein to include at least one, such as 1-30, or 1-20 or 1-10, such as 1 or 2 or 3 or 4 or 5 amino acid substitutions or deletions. And/or an antibody inserted into the target antibody region with amino acid changes (for example, a heavy chain variable region or a light chain variable region or a heavy chain CDR region or a light chain CDR region), wherein the variant basically retains the antibody molecule before the change Biological characteristics.
  • the invention encompasses variants of any of the antibodies described herein.
  • the antibody variant retains at least 60%, 70%, 80%, 90%, or 100% of the biological activity (eg, antigen binding ability) of the antibody before the change.
  • variable region of the heavy chain or the variable region of the light chain, or each CDR region of an antibody can be changed individually or in combination.
  • amino acid changes are amino acid substitutions, preferably conservative substitutions.
  • substitution refers to the substitution of an amino acid by another amino acid in the same category, for example, an acidic amino acid is substituted by another acidic amino acid, a basic amino acid is substituted by another basic amino acid, or a neutral amino acid is substituted by another Neutral amino acid substitution. Exemplary substitutions are shown in the following table:
  • the antibody variant has at least 80%, 90% or 95% or 99% or higher amino acid identity with the parent antibody in the sequence region of the antibody of interest.
  • vector when used herein refers to a nucleic acid molecule capable of multiplying another nucleic acid to which it is linked.
  • the term includes vectors that are self-replicating nucleic acid structures as well as vectors that are incorporated into the genome of a host cell into which it has been introduced. Some vectors can direct the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors”.
  • host cell refers to cells into which exogenous nucleic acid is introduced, including the progeny of such cells.
  • Host cells include “transformants” and “transformed cells”, which include primary transformed cells and progeny derived therefrom, regardless of the number of passages.
  • the offspring may not be exactly the same as the parent cell in nucleic acid content, but may contain mutations.
  • the progeny of mutants having the same function or biological activity as those screened or selected in the initially transformed cells are included herein.
  • Suitable host cells for cloning or expressing antibody-encoding vectors include prokaryotic or eukaryotic cells described herein.
  • antibodies can be produced in bacteria, especially when glycosylation and Fc effector functions are not required.
  • the antibody After expression, the antibody can be separated from the bacterial cell paste in the soluble fraction and can be further purified.
  • the host cell is eukaryotic.
  • the host cell is selected from yeast cells, mammalian cells, or other cells suitable for preparing antibodies or antigen-binding fragments thereof.
  • eukaryotic microorganisms such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungal and yeast strains, whose glycosylation pathways have been "humanized", resulting in the production of partially or completely human Antibodies with glycosylation patterns. See Gerngross, Nat. Biotech. 22: 1409-1414 (2004), and Li et al., Nat. Biotech. 24: 210-215 (2006).
  • Host cells suitable for expressing glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Vertebrate cells can also be used as hosts.
  • a mammalian cell line modified to be suitable for growth in suspension can be used.
  • useful mammalian host cell lines are monkey kidney CV1 line (COS-7) transformed with SV40; human embryonic kidney line (293 or 293 cells, such as, for example, Graham et al., J. Gen Virol. 36:59 (1977) Described in) and so on.
  • Other useful mammalian host cell lines include Chinese Hamster Ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., Proc. Natl. Acad.
  • an “isolated” antibody is an antibody that has been separated from a component of its natural environment.
  • the antibody is purified to more than 95% or 99% purity, such as by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC) confirmed.
  • electrophoresis e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis
  • chromatography e.g., ion exchange or reverse phase HPLC
  • nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment.
  • An isolated nucleic acid includes a nucleic acid molecule contained in a cell that normally contains the nucleic acid molecule, but the nucleic acid molecule exists outside the chromosome or at a chromosomal location different from its natural chromosomal location.
  • the "percent (%) amino acid sequence identity" relative to the reference polypeptide sequence is defined as when the sequence is aligned (and gaps are introduced when necessary) to obtain the maximum percent sequence identity, and any conservative substitutions are not considered After being part of sequence identity, the percentage of amino acid residues in the candidate sequence that are identical to those in the reference polypeptide sequence.
  • sequence alignment can be used for sequence alignment to determine percent amino acid sequence identity, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for the measurement alignment, including any algorithm required to obtain the maximum alignment over the entire length of the sequence being compared.
  • Affinity or "binding affinity” refers to the inherent binding affinity that reflects the interaction between members of a binding pair (eg, antibody and antigen).
  • the affinity of a molecule X to its partner Y can usually be expressed by the equilibrium dissociation constant (K D ).
  • the equilibrium dissociation constant is the ratio of the dissociation rate constant and the association rate constant (k dis and k on, respectively ). Affinity can be measured by common methods known in the art, including those known in the prior art and those described herein.
  • Immunoconjugate refers to an antibody conjugated to one or more heterologous molecules, including but not limited to a carrier.
  • composition refers to a formulation that exists in a form that allows the biological activity of the active ingredients contained therein to be effective, and does not contain additional ingredients that have unacceptable toxicity to the subject to which the formulation is administered .
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more monoclonal antibodies that bind to VZV or immunologically active fragments thereof.
  • the anti-VZV antibody or pharmaceutical composition provided by the present invention can be integrated into suitable carriers, excipients and other agents in the formulation for combined administration, thereby providing improved transfer, delivery, tolerance and the like.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant (for example, Freund's adjuvant (complete and incomplete)), excipient, or vehicle that is administered with the therapeutic agent.
  • Pharmaceutical carriers suitable for use in the present invention may be conventional, see “Handbook of Pharmaceutical Excipients”, seventh edition, RC Rowe, PJSeskey and SCOwen, Pharmaceutical Press, London, Chicago, described pharmaceutical preparation excipients; and “Remington's Pharmaceutical Sciences” EW Martin, Mack Publishing Co, Easton, PA Publishing, 21st edition, 2012, describes compositions and formulations suitable for drug delivery of the disclosed antibodies.
  • parenteral preparations usually include an injectable fluid as a carrier, and the injectable fluid includes pharmaceutically acceptable and physiologically acceptable liquids, such as water, physiological saline, emulsions in oily or aqueous media, etc., and may contain formulations, For example, suspending agents, preservatives, excipients, stabilizers, surfactants, chelating agents and/or binders.
  • the pharmaceutically acceptable carrier also includes low molecular weight polypeptides, proteins (e.g., serum albumin and gelatin), amino acids (e.g., glycine, glutamine, asparagine, glutamate, aspartame).
  • Acid, methionine, arginine, and lysine sugars and carbohydrates (e.g., polysaccharides and monosaccharides), and sugar alcohols (e.g., mannitol and sorbitol).
  • physiological saline and an isotonic solution including glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride can be used, and if necessary, with appropriate Solubilizers such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol and PEG), and nonionic surfactants (e.g., polysorbate 80, polysorbate 20, poloxamer 188, and HCO -50) Used in combination.
  • conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • the solid composition may also be formulated as an injectable fluid in a liquid medium prior to administration (for example, the lyophilized composition Herceptin (TM )).
  • the pharmaceutical combination of the present invention can be administered through various routes, including but not limited to oral, intravenous, intramuscular, intratracheal, transdermal, topical, intranasal, and other administration methods.
  • an effective amount refers to an amount or dose sufficient to obtain or at least partially obtain the desired effect after administration in a single or multiple doses
  • therapeutically effective amount refers to an amount that produces the desired effect in the treated subject, including Improvement of the subject’s symptoms (for example, improvement of one or more symptoms) and/or delay of the progression of symptoms, etc.
  • An effective amount for preventing diseases refers to an amount sufficient to prevent, prevent, or delay the occurrence of diseases.
  • the therapeutically effective amount depends on the specific disease involved; the degree or severity of the disease; the response of the individual patient; the specific antibody administered; the mode of administration; the organism to which the preparation is administered Utilization characteristics; selected dosing regimen; and use of any concomitant therapy, etc.
  • treatment refers to slowing, interrupting, blocking, alleviating, stopping, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.
  • thickenpox refers to an acute infectious disease caused by the first infection of varicella-zoster virus (VZV), which is mainly characterized by fever and mass appearance of red macules, herpes, and scabs.
  • VZV varicella-zoster virus
  • herpes zoster refers to a condition in which the VZV virus lurking in the ganglion is reactivated and proliferates along the nerve axis to the skin innervated by the nerve.
  • subject or “individual” is a primate (e.g., human and non-human primates such as monkeys). In certain embodiments, the individual or subject is a human.
  • primate e.g., human and non-human primates such as monkeys.
  • the individual or subject is a human.
  • Table I The heavy chain variable region sequence and light chain variable region sequence of each antibody:
  • VZV gH/gL protein complex (CAMBRIDGEBIO, Cat No: 01-11-0045) was selected as the antigen for serum antibody titer ELISA test, and the sample with the highest antibody titer change significantly changed (diluted 50 times, OD value) >2.0) Perform streaming sorting.
  • the antibody gene was isolated by the following PCR program: The first round of PCR: 50ul system contains 5ul of reverse transcription reaction product, 5 units of Taq enzyme, 0.2mM dNTPs, and 0.5uM of each subtype heavy chain and light chain Antibody constant region primers (sequence), reaction conditions: pre-denaturation at 95°C for 5min, then 35 PCR cycles, each cycle: 95°C ⁇ 30s, 55°C ⁇ 60s, 72°C ⁇ 90s, and finally extended at 72°C for 7min .
  • the second round of PCR The 50ul system contains 2.5ul of the first round of PCR reaction product, 5 units of TaqPlus enzyme, 0.2mM dNTPs, and 0.5uM of each subtype heavy chain and light chain antibody variable region primers, reaction Conditions: pre-denaturation at 95°C for 5 minutes, and then 35 PCR cycles, each cycle is: 95°C ⁇ 30s, 58°C ⁇ 60s, 72°C ⁇ 90s, and finally extended at 72°C for 7 minutes.
  • the obtained PCR products were identified by 1.2% agarose gel electrophoresis.
  • the PCR product of the antibody gene identified as positive, and the heavy chain and the light chain can be matched in pairs are purified with the Qiagen PCR product purification kit, and the sequence is determined from the forward and reverse directions respectively, using the IMGT online server (http:/ /imgt.cines.fr/) to analyze.
  • the obtained PCR product of the antibody variable region gene was ligated to the pcDNA3.3 vector containing human IgG1 constant region by TA cloning method to construct an expression vector of fully human neutralizing antibody against varicella-zoster virus, and then The expression vector was transformed into DH5 ⁇ competent bacteria for vector amplification and the recombinant plasmid was extracted.
  • the obtained recombinant plasmid and the transfection reagent PolyFect were co-transfected into HEK293 cells and cultured in a 37°C, 8% CO 2 incubator. The paired heavy chain and light chain gene expression vectors were expressed in the cells. After 96 hours of culture, the supernatant was collected.
  • the cell debris was discarded by centrifugation, and the supernatant was purified by Protein A affinity chromatography.
  • the purified antibodies were tested by SDS-PAGE. The results are shown in Figure 1.
  • the non-reduced bands of antibodies TRN1024, TRN1025, and TRN1026 are between 135-180KD. After reduction, clear heavy and light chain bands are obtained, which is the purpose.
  • Antibodies-Recombinant fully human neutralizing antibodies against varicella-zoster virus.
  • an ELISA test was used to detect the binding activity of the recombinant antibodies obtained in the above examples. Coat the ELISA 96-well plate with 100ng/well VZV gH/gL protein complex at 4°C overnight, and then block with blocking solution at room temperature for 2 hours. Then, 100 uL of the recombinant antibody HEK293 cell culture supernatant of the present invention and a negative control (anti-rabies virus antibody TRN006, that is, an antibody unrelated to VZV) were added to the 96-well plate, and incubated for 1 h at 37°C.
  • a negative control anti-rabies virus antibody TRN006, that is, an antibody unrelated to VZV
  • the surface plasmon resonance technique (the instrument is BIACORE3000) is used to measure the KD value of the antibody of the present invention.
  • Use the CM5 chip to couple the capture molecules, activate the dextran surface of the chip, and determine the coupling amount with the injection time.
  • Use BiaCore X-100System software for analysis. Specific steps are as follows:
  • the anti-human IgG (Fc) was coupled to the two channels of the CM5 chip by amino coupling.
  • the concentration of captured TRN1024, TRN1025 and TRN1026 was 1 ⁇ g/mL, and the binding time was 60s.
  • the concentration of the bound VZV gH/gL protein complex is shown in Figure 3. The minimum is 1.56 ⁇ g/mL and the maximum is 200 ⁇ g/mL, the binding time is 90s, and the dissociation time is 600s.
  • the regeneration solution is 3M MgCl 2 , and the regeneration time is 30s.
  • association rate (ka), dissociation rate (kd), and equilibrium dissociation constant were calculated by fitting the association and dissociation sensorgrams ( Figure 3) at the same time.
  • the results are shown in the following table.
  • Human embryonic lung fibroblasts (MRC-5) were used to detect the neutralizing activity of the antibody.
  • the infected cells are detected by enzyme-linked immunospot method.
  • the number of positive cells with signal is the number of infected cells, which can be considered as the number of infected units of VZV virus used in the infection experiment.
  • the titer of VZV virus was detected by the method of gradient dilution spot counting.
  • the above-mentioned infected MRC-5 cells were digested by conventional methods, and then plated on 96-well plates for conventional culture in preparation for the next day's neutralization experiment.
  • the antibody of the present invention can obviously neutralize the activity of the VZV Oka standard strain and inhibit the apoptosis of MRC-5 cells; the control without the addition of the antibody cannot neutralize the activity of the virus.
  • the neutralizing titer of the three strains of TRN1024, TRN1025, and TRN1026 antibodies can reach 1.56ug/mL. It shows that these three antibodies can specifically recognize the cells infected by the VZV virus, and play a role in neutralizing the virus and inhibiting the spread of the virus between cells.
  • Hep-2 cells are human laryngeal cancer epithelial cells. Because of their rich antigen spectrum (about 100-150 types), strong antigen specificity and high antigen content, the international standard method for detecting antinuclear antibodies is usually Hep-2 Indirect immunofluorescence with cells as substrates. In this embodiment, the immunofluorescence method is used to detect the staining reaction of the antibody on the Hep2 cells to determine whether the antibody has an autoimmune response.
  • Use anti-nuclear antibody (ANA) detection kit 200 people for detection, fluorescence microscope observation. The results are shown in Figure 4.
  • TRN1024, TRN1025, and TRN1026 antibodies did not have specific fluorescence (GFP), that is, the antibodies did not interact with Hep-2 cells. Antigen binding; while in the positive control group, obvious GFP fluorescence was observed. This indicates that the antibody of the present invention has no autoimmune response to Hep-2 cells.
  • herpes fluids from patients with varicella or herpes zoster virus for clinical sample virus isolation (see Liu J, Wang M, Gan L et al. Genotyping of Clinical Varicella-Zoster Virus Isolates Collected in China[J]. Journal of Clinical Microbiology,2009,47(5):1418-1423./Liu J J, Wang M L, Gan L et al.
  • This example explores the preventive function of the three antibodies of TRN1024, TRN1025, and TRN1026 against VZV Oka strain virus infection in vivo.
  • the applicant has discovered that one or more substitutions (such as conservative substitutions), insertions or deletions of amino acid sequences have been introduced into the framework regions of the heavy chain variable region and/or light chain variable region sequence. Modifications will not substantially affect the binding ability of the variable region to antigen.
  • the heavy chain variable region sequence (VH) of the antibody TRN1026 is shown in SEQ ID NO: 23, and the light chain variable region sequence (VL) is shown in SEQ ID NO: 24.
  • one or more substitutions are introduced into the framework region of the variable region of antibody TRN1026, and the obtained derivative antibody still retains the binding activity of the anti-VZV antibody .
  • an antibody derived from TRN1026 with a VH shown in SEQ ID NO: 25 and a VL shown in SEQ ID NO: 26, and the culture supernatant is taken to perform an EILISA experiment to detect its binding activity after expression.
  • the results show that the TRN1026 antibody derivative and the VZV gH/gL protein complex still maintain the binding activity, with an EC50 as low as 0.05ug/mL. It can be seen that one or more substitutions (such as conservative substitutions) have been made to the framework regions of the antibody variable regions. ), the insertion or deletion of amino acid modifications will not affect the activity and function of the recombinant antibody.

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN117683121A (zh) * 2024-01-30 2024-03-12 北京百普赛斯生物科技股份有限公司 抗水痘-带状疱疹病毒抗体及其应用
CN117683121B (zh) * 2024-01-30 2024-04-16 北京百普赛斯生物科技股份有限公司 抗水痘-带状疱疹病毒抗体及其应用

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