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CN-122011175-A - Neutralizing antibody against human parainfluenza virus 3 and use thereof

CN122011175ACN 122011175 ACN122011175 ACN 122011175ACN-122011175-A

Abstract

The present application provides antibodies against human parainfluenza virus type 3, bispecific antibodies against human parainfluenza virus type 3 and respiratory syncytial virus, nucleic acid molecules encoding said antibodies and/or bispecific antibodies, vectors comprising said nucleic acid molecules, host cells comprising said nucleic acid molecules or vectors, and pharmaceutical compositions comprising said antibodies and/or bispecific antibodies. The application also provides methods of making and purifying the antibodies and/or bispecific antibodies and uses of the antibodies and/or bispecific antibodies.

Inventors

  • FU XINLEI
  • LIU ZHIGANG
  • ZHOU XIAOWEI
  • HAO XIAOBO
  • LIU YULAN
  • HU JUNJIE

Assignees

  • 北京智仁美博生物科技有限公司

Dates

Publication Date
20260512
Application Date
20241108

Claims (10)

  1. 1. An antibody against human parainfluenza virus type 3 (HPIV 3) comprising a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 and a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein The amino acid sequence of the HCDR1 is shown as SEQ ID NO. 1, the amino acid sequence of the HCDR2 is shown as SEQ ID NO. 2, the amino acid sequence of the HCDR3 is shown as SEQ ID NO. 3, the amino acid sequence of the LCDR1 is shown as SEQ ID NO. 4, the amino acid sequence of the LCDR2 is shown as SEQ ID NO. 5 and the amino acid sequence of the LCDR3 is shown as SEQ ID NO. 6; wherein the HCDR and LCDR amino acid sequences are defined according to Kabat.
  2. 2. The antibody of claim 1, wherein the amino acid sequence of the heavy chain variable region of the antibody has at least 90% identity to SEQ ID No. 7 and/or the amino acid sequence of the light chain variable region of the antibody has at least 90% identity to SEQ ID No. 8; Preferably, the amino acid sequence of the heavy chain variable region of the antibody is shown in SEQ ID NO. 7 and/or the amino acid sequence of the light chain variable region of the antibody is shown in SEQ ID NO. 8.
  3. 3. The antibody of any one of claims 1-2, wherein The antibody is a neutralizing antibody, and/or The antibody is capable of binding to the F protein of HPIV3, preferably the antibody is capable of binding to the recombinant human HPIV 3F protein as shown in SEQ ID NO 9, and/or The antibody is a Fab fragment, a whole antibody, a F (ab') 2 fragment or a single chain Fv fragment (scFv), preferably the antibody is a Fab fragment, and/or The antibody is a monoclonal antibody.
  4. 4. The antibody of any one of claims 1-3, wherein The antibody further comprises a heavy chain constant region selected from the group consisting of an IgG1 subtype, an IgG2 subtype, and an IgG4 subtype, preferably the heavy chain constant region comprises an Fc segment sequence of an IgG1 subtype heavy chain constant region and the amino acid sequences at positions 252,254,256 of the Fc segment sequence are Y, T, and E, respectively, wherein the antibody constant region amino acid sequence is determined according to EU numbering, and/or The antibody further comprises a light chain constant region selected from the kappa subtype or the lambda subtype, preferably the light chain constant region is of the kappa subtype.
  5. 5. A bispecific antibody against human parainfluenza virus type 3 (HPIV 3) and Respiratory Syncytial Virus (RSV), the bispecific antibody comprising a first antigen-binding region that binds HPIV3 and a second antigen-binding region that binds RSV, wherein the first antigen-binding region comprises a heavy chain variable region comprising HCDR1 having an amino acid sequence as shown in SEQ ID No.1, HCDR2 having an amino acid sequence as shown in SEQ ID No.2, HCDR3 having an amino acid sequence as shown in SEQ ID No. 3, and a light chain variable region comprising LCDR1 having an amino acid sequence as shown in SEQ ID No.4, LCDR2 having an amino acid sequence as shown in SEQ ID No. 5, and LCDR3 having an amino acid sequence as shown in SEQ ID No. 6; Optionally, the second antigen binding region comprises a heavy chain variable region comprising HCDR1 having an amino acid sequence as set forth in SEQ ID NO. 34, HCDR2 having an amino acid sequence as set forth in SEQ ID NO. 35, HCDR3 having an amino acid sequence as set forth in SEQ ID NO. 36, and a light chain variable region comprising LCDR1 having an amino acid sequence as set forth in SEQ ID NO. 37, LCDR2 having an amino acid sequence as set forth in SEQ ID NO. 38, and LCDR3 having an amino acid sequence as set forth in SEQ ID NO. 39; wherein the HCDR and LCDR amino acid sequences are defined according to Kabat.
  6. 6. The bispecific antibody of claim 5, wherein the amino acid sequence of the heavy chain variable region of the first antigen binding region has at least 90% identity to SEQ ID NO. 7, or the amino acid sequence of the heavy chain variable region of the first antigen binding region is shown as SEQ ID NO. 7, and/or the amino acid sequence of the light chain variable region of the first antigen binding region has at least 90% identity to SEQ ID NO. 8, or the amino acid sequence of the light chain variable region of the first antigen binding region is shown as SEQ ID NO. 8; Optionally, the amino acid sequence of the heavy chain variable region of the second antigen binding region has at least 90% identity to SEQ ID NO. 41, or the amino acid sequence of the heavy chain variable region of the second antigen binding region is shown as SEQ ID NO. 41, and/or the amino acid sequence of the light chain variable region of the second antigen binding region has at least 90% identity to SEQ ID NO. 42, or the amino acid sequence of the light chain variable region of the second antigen binding region is shown as SEQ ID NO. 42.
  7. 7. The bispecific antibody of any one of claims 5-6, wherein the bispecific antibody is capable of binding to the F protein of HPIV3 and/or the F protein of RSV, preferably the bispecific antibody is capable of binding to the recombinant human HPIV 3F protein as shown in SEQ ID No. 9 and/or the recombinant RSV F protein as shown in SEQ ID No. 40.
  8. 8. A nucleic acid molecule encoding the antibody of any one of claims 1-4 and/or the bispecific antibody of any one of claims 5-7.
  9. 9. A pharmaceutical composition comprising the antibody of any one of claims 1-4 and/or the bispecific antibody of any one of claims 5-7 and a pharmaceutically acceptable excipient, diluent or carrier.
  10. 10. Use of the antibody of any one of claims 1-4, the bispecific antibody of any one of claims 5-7, the nucleic acid molecule of claim 8, or the pharmaceutical composition of claim 9 in the manufacture of a medicament for the prevention or treatment of HPIV3 infection and related diseases, or use of the bispecific antibody of any one of claims 5-7, the nucleic acid molecule of claim 8 encoding the bispecific antibody, or the pharmaceutical composition of claim 9 comprising the bispecific antibody in the manufacture of a medicament for the prevention or treatment of RSV infection and related diseases; preferably, the HPIV3 infection-related disease is a respiratory tract infection caused by HPIV3 infection, more preferably, the HPIV3 infection-related disease is bronchitis, bronchiolitis or pneumonia caused by HPIV3 infection, and/or The RSV infection-related disease is a respiratory tract infection caused by an RSV infection, more preferably, the RSV infection-related disease is bronchiolitis or pneumonia caused by an RSV infection.

Description

Neutralizing antibody against human parainfluenza virus 3 and use thereof Technical Field The present application relates generally to the field of genetic engineering and antibody pharmaceuticals, and in particular to bispecific antibodies directed against human parainfluenza virus type 3 (HPIV 3) antibodies, against human parainfluenza virus type 3 (HPIV 3) and Respiratory Syncytial Virus (RSV) and the use of said antibodies in the prevention or treatment of HPIV3 infection and related diseases and the use of said bispecific antibodies in the prevention or treatment of HPIV3 infection and related diseases and RSV infection and related diseases. Background Human parainfluenza virus (human parainfluenza virus, HPIV) is one of the major pathogens responsible for lower respiratory tract infections in children, at least 75% -85% of children under 5 years of age having been infected with HPIV [1]. HPIV can be classified into types 1-4 based on viral genetics and antigenicity, and HPIV-4 can be classified into subtypes A and B [2]. Of these, human parainfluenza virus type 3 (human parainfluenza virus type, HPIV3) acts as a major respiratory virus, causing acute respiratory infections, with childhood infection rates inferior to Respiratory Syncytial Virus (RSV). HPIV3 primarily infects newborns, infants and immunocompromised adults, causing pneumonia and bronchitis. Unlike other HPIV, 40% of HPIV3 infections occur in the first year after birth. There are study statistics that about 6.8% of cases in which children under 5 years of the united states are hospitalized due to acute respiratory infections are caused by HPIV infections, with HPIV3 accounting for over half of them, and that HPIV infections are estimated to cause about 23,000 cases [3] hospitalized for children under 5 years of the year each year. HPIV is a class of enveloped, non-segmented, single-stranded negative-strand RNA viruses of Paramyxoviridae. Typically spherical, with a diameter of 125-250 nm, the genome is about 15,500bp in length, encoding 6 structural proteins, including 2 membrane glycoproteins, hemagglutinin-neuraminidase (HN) and fusion protein (F), and 4 intramembrane proteins, matrix protein (M), nucleocapsid protein (nucleocapsid protein, N), phosphoprotein (phosphoprotein, P) and RNA polymerase (large RNA polymerase protein, L) [4]. Among them, HN protein and F protein are main protective antigens on the surface of viral envelope, and can induce host to produce neutralizing antibody. The F protein regulates membrane fusion, promotes entry of viral nucleocapsids into host cells, while HN has hemagglutinin (hemagglutinin, HI) and Neuraminidase (NA) activity [1]. HPIV fuses the viral envelope with the host cell membrane by the synergistic effect of the F protein and HN, and upon binding of HN to Sialic Acid (SA), the metastable pre-fusion form of the F protein is activated, undergoes a series of structural rearrangements, and becomes a stable post-fusion form, driving fusion between membranes. It has been found that the glycosylation sites and numbers of HN are not identical across different viral subtypes, whereas the F protein is highly conserved [5] across different viral subtypes. At present, no vaccine and medicine aiming at HPIV3 are marketed at home and abroad, and based on clinical requirements, the development of an anti-HPIV 3 antibody and a bispecific antibody for resisting HPIV3 and RSV has important biological and medical significance for preventing or treating HPIV3 infection and RSV infection and related diseases caused by the same. Summary of The Invention In a first aspect, the application provides an antibody to human parainfluenza virus type 3 (HPIV 3) comprising a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 and a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein The amino acid sequence of the HCDR1 is shown as SEQ ID NO. 1, the amino acid sequence of the HCDR2 is shown as SEQ ID NO. 2, the amino acid sequence of the HCDR3 is shown as SEQ ID NO. 3, the amino acid sequence of the LCDR1 is shown as SEQ ID NO. 4, the amino acid sequence of the LCDR2 is shown as SEQ ID NO. 5 and the amino acid sequence of the LCDR3 is shown as SEQ ID NO. 6; wherein the HCDR and LCDR amino acid sequences are defined according to Kabat. In some embodiments of the first aspect, the amino acid sequence of the heavy chain variable region of the antibody is set forth in SEQ ID NO. 7. In some embodiments of the first aspect, the amino acid sequence of the light chain variable region of the antibody is set forth in SEQ ID NO. 8. In some embodiments of the first aspect, the amino acid sequence of the heavy chain variable region of the antibody is shown in SEQ ID NO. 7 and the amino acid sequence of the light chain variable region of the antibody is shown in SEQ ID NO. 8. In some embodiments of the first aspect, the amino acid sequence of the heavy chain variable region of the antibody has at least 90% identit