WO2023036982A1 - Anticorps anti-sars2-s - Google Patents

Anticorps anti-sars2-s Download PDF

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Publication number
WO2023036982A1
WO2023036982A1 PCT/EP2022/075284 EP2022075284W WO2023036982A1 WO 2023036982 A1 WO2023036982 A1 WO 2023036982A1 EP 2022075284 W EP2022075284 W EP 2022075284W WO 2023036982 A1 WO2023036982 A1 WO 2023036982A1
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Prior art keywords
seq
sars2
sequence
light chain
heavy chain
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PCT/EP2022/075284
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English (en)
Inventor
Franklin Gerardus Grosveld
Berend Jan Bosch
Bartholomeus Leonard HAAGMANS
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Harbour Antibodies Bv
Universiteit Utrecht Holding Bv
Erasmus University Medical Center Rotterdam
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Priority claimed from GBGB2112933.3A external-priority patent/GB202112933D0/en
Application filed by Harbour Antibodies Bv, Universiteit Utrecht Holding Bv, Erasmus University Medical Center Rotterdam filed Critical Harbour Antibodies Bv
Publication of WO2023036982A1 publication Critical patent/WO2023036982A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1002—Coronaviridae
    • C07K16/1003—Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2 or Covid-19]
    • 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
    • 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

Definitions

  • the invention relates to antibodies and antigen-binding fragments thereof that recognize the spike (S) protein of SARS-Cov-2 coronavirus (Covid-19), hereafter called SARS2 or SARS-CoV-2.
  • SARS-Cov-2 coronavirus Covid-19
  • Coronavirus disease 19 (COVID-19) is caused by the zoonotic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • SARS-CoV-2 zoonotic severe acute respiratory syndrome coronavirus 2
  • the virus infects humans and human-to-human transmission is efficient, it occurs at close contact and via airway expelled micro-droplets. It is a lower airway infection with fever, coughing and shortness of breath as the primary symptoms and leads in ⁇ 2% of cases to a lethal pneumonia.
  • Elderly people and patients with an impaired immune system are particularly vulnerable, (the WHO, in 2020).
  • SARS-CoV-2 belongs to the Sarbecovirus subgenus along with another zoonotic coronavirus SARS-CoV1 (originally termed SARS-CoV; hereafter referred to as SARS-1 or SARS- CoV-1) that emerged in 2002/2003 displaying a ⁇ 10% fatality rate.
  • SARS-CoV2 spike protein SARS2-S
  • the invention provides an anti-SARS2-S antibody comprising complementarity determining regions (CDRs) with the sequences of: i. a sequence that is at least 90% identical to SEQ ID NO: 1 for CDR1 of the heavy chain; ii. a sequence that is at least 90% identical to SEQ ID NO: 2 for CDR2 of the heavy chain; iii. a sequence that is at least 90% identical to SEQ ID NO: 3 for CDR3 of the heavy chain; iv. a sequence that is at least 90% identical to SEQ ID NO: 4 for CDR1 of the light chain; v. a sequence that is at least 90% identical to SEQ I D NO: 5 for CDR2 of the light chain; and vi. a sequence that is at least 90% identical to SEQ I D NO: 6 for CDR3 of the light chain.
  • CDRs complementarity determining regions
  • the invention further provides a fully human monoclonal IgG 1 anti-SARS2-S antibody consisting of two heavy and two light chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 1 for CDR1 of the heavy chain; ii. SEQ ID NO: 2 for CDR2 of the heavy chain; and iii. SEQ ID NO: 3 for CDR3 of the heavy chain; and wherein each light chain comprises CDRs with the sequences of: iv. SEQ ID NO: 4 for CDR1 of the light chain; v. SEQ ID NO: 5 for CDR2 of the light chain; and vi. SEQ ID NO: 6 for CDR3 of the light chain.
  • CDRs complementarity determining regions
  • the invention further provides a fully human monoclonal IgG 1 anti-SARS2-S antibody consisting of two heavy and two light chains, wherein each heavy chain comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7, and wherein each light chain comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 8.
  • the invention further provides a fully human monoclonal IgG 1 anti-SARS2-S antibody consisting of two heavy and two light chains, wherein each heavy chain has the amino acid sequence of SEQ ID NO: 9, and wherein each light chain has the amino acid sequence of SEQ ID NO: 10.
  • the invention further provides an anti-SARS2-S antibody that comprises complementarity determining regions (CDRs) with the sequences of:
  • the invention further provides an anti-SARS2-S antibody that comprises:
  • the invention further provides a fully human monoclonal IgG 1 anti-SARS2-S antibody consisting of two heavy and two light chains, wherein:
  • each heavy chain comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 24, and wherein each light chain comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 25,
  • each heavy chain comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 26, and wherein each light chain comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 27,
  • each heavy chain comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 28, and wherein each light chain comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 29,
  • each heavy chain comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 30, and wherein each light chain comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 31 ,
  • each heavy chain comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 32, and wherein each light chain comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 33,
  • each heavy chain comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 34, and wherein each light chain comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 35,
  • each heavy chain comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 36, and wherein each light chain comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 37
  • each heavy chain comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 38
  • each light chain comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 39
  • each heavy chain comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 40, and wherein each light chain comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 41 , or
  • each heavy chain comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 42, and wherein each light chain comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 43.
  • the invention further provides a fully human monoclonal IgG 1 anti-SARS2-S antibody consisting of two heavy and two light chains, wherein:
  • each heavy chain has the amino acid sequence of SEQ ID NO: 44, and wherein each light chain has the amino acid sequence of SEQ ID NO: 45,
  • each heavy chain has the amino acid sequence of SEQ ID NO: 46, and wherein each light chain has the amino acid sequence of SEQ ID NO: 47,
  • each heavy chain has the amino acid sequence of SEQ ID NO: 60, and wherein each light chain has the amino acid sequence of SEQ ID NO: 61 ,
  • each heavy chain has the amino acid sequence of SEQ ID NO: 62, and wherein each light chain has the amino acid sequence of SEQ ID NO: 63,
  • each heavy chain has the amino acid sequence of SEQ ID NO: 64, and wherein each light chain has the amino acid sequence of SEQ ID NO: 65,
  • each heavy chain has the amino acid sequence of SEQ ID NO: 66, and wherein each light chain has the amino acid sequence of SEQ ID NO: 67,
  • each heavy chain has the amino acid sequence of SEQ ID NO: 68, and wherein each light chain has the amino acid sequence of SEQ ID NO: 69,
  • each heavy chain has the amino acid sequence of SEQ ID NO: 70, and wherein each light chain has the amino acid sequence of SEQ ID NO: 71 ,
  • each heavy chain has the amino acid sequence of SEQ ID NO: 72, and wherein each light chain has the amino acid sequence of SEQ ID NO: 73, or
  • each heavy chain has the amino acid sequence of SEQ ID NO: 74, and wherein each light chain has the amino acid sequence of SEQ ID NO: 75.
  • the invention further provides a combination of antibodies comprising: (i) a first anti-SARS2-S antibody, wherein the antibody is according to the invention, and
  • the invention further provides an isolated nucleic acid encoding an antibody of the invention.
  • the invention further provides a vector comprising a nucleic acid of the invention.
  • the invention further provides a host cell comprising a vector of the invention.
  • the invention further provides a pharmaceutical composition comprising an antibody of the invention, or a combination of antibodies of the invention, and a pharmaceutically acceptable carrier.
  • the invention further provides an antibody, combination of antibodies or composition of the invention for use in therapy, optionally wherein the therapy is preventing, treating or ameliorating coronavirus infection, optionally betacoronavirus infection, such as SARS2 infection.
  • the invention further provides a fully human monoclonal IgG 1 anti-SARS2-S antibody consisting of two heavy and two light chains, wherein each heavy chain comprises complementarity determining regions (CDRs) with the sequences of: i. SEQ ID NO: 1 for CDR1 of the heavy chain; ii. SEQ ID NO: 2 for CDR2 of the heavy chain; and iii. SEQ ID NO: 3 for CDR3 of the heavy chain; and wherein each light chain comprises CDRs with the sequences of: iv. SEQ ID NO: 4 for CDR1 of the light chain; v. SEQ ID NO: 5 for CDR2 of the light chain; and vi. SEQ ID NO: 6 for CDR3 of the light chain, for use in preventing, treating or ameliorating SARS2 infection in a human subject, wherein the antibody prevents, treats or ameliorates:
  • CDRs complementarity determining regions
  • SARS2 replication optionally SARS2 replication in the lower respiratory tract, and/or
  • the invention further provides a fully human monoclonal IgG 1 anti-SARS2-S antibody consisting of two heavy and two light chains, wherein each heavy chain comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7, and wherein each light chain comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 8, for use in preventing, treating or ameliorating SARS2 infection in a human subject, wherein the antibody prevents, treats or ameliorates:
  • SARS2 replication optionally SARS2 replication in the lower respiratory tract, and/or
  • the invention further provides a method for producing anti-SARS2-S antibodies comprising:
  • SARS2 spike protein subunit e.g. monomeric S1 B
  • SARS2-S ectodomain e.g. trimeric SARS2-S ec to
  • NTD N-terminal domain
  • RBD receptor binding domain
  • TM transmembrane domain
  • H2L2 mice were immunized with cDNA of the spike protein cloned in pCAGG by intradermal electroporation (3x) followed by protein immunization with the SED domain of the SARS2 spike (6x).
  • the titer of the serum was determined using a standard ELISA assay. 273 positive hybridomas were identified from 5000 clones. Exemplary ELISA results for SED and S1B domain binding are shown in the top and bottom graphs, respectively.
  • Figure 3 Spike protein mutations of SARS-CoV-2 variants of concern
  • B Spike residues in the receptor binding domain (RBD) that are at variance in the B.1.1.7 (UK), B.1.351 (SA) and P.1 (BR) variants - K417N/T, E484K and N501Y - are positioned at the ACE2 binding interface.
  • 87G7 (in H2L2 format) was tested in comparison to the Regeneron 10987 antibody in a pseudovirus blocking assay using different mutations in the spike protein. The results show that 87G7 compares very well with the Regeneron antibody REGN 10987 and is a potent blocker of the most serious mutation E484K.
  • 87G7 (in human lgG1 format) was tested in comparison to the S309, REGN10987, and REGN10933 antibodies in a pseudo-virus blocking assay using the L452R mutation in the spike protein. The results show that 87G7 is a potent blocker of the L452R mutant.
  • the L452R mutation is found in the B.1.617.2 (India) variant SARS2-S.
  • the 87G7 antibody was tested in competition assays against the 66b12 and 79a7 and the control antibodies REGN 10933, REGN 10987, S309 and CR3022. This is carried out by binding a first antibody to saturation to the spike protein followed by a wash and binding of the second antibody. If the second protein is able to bind it shows that the binding site is different whereas no further binding shows that the first and second antibody bind to the same region of the spike protein. The results show that the binding site of 87G7 on the spike protein overlaps with REGN 10933, 66B12 and 79A7 and binding of the receptor protein ACE2.
  • the binding site of 87G7 on the spike protein overlaps with REGN 10933, 66B12 and 79A7 and binding of the receptor protein ACE2. However, the binding site of 87G7 does not overlap with REGN 10987, S309, CR3022 or 47D11.
  • Wildtype (Wuhan) SARS-CoV-2 or the variants of concern (B.1.1.7 (UK) and B.1.351 (SA)) were preincubated with indicated antibodies at indicated concentrations prior to infection of Vero cells. Infection (%) was calculated relative to non-antibody-treated controls. The results for wildtype, B.1.1.7 and B.1.351 are shown in (A), (B) and (C), respectively.
  • Figure 14 VH and VL sequences of 87G7 and other anti-SARS2-S antibodies
  • VH and L domain sequences of 87G7, 21 E1 , 83E6 also known as 85A9, 85H3, 86E5, 88G9, 90C5, 80A4 (also known as 85F8), 90A1, 66B12 and 79A7.
  • VH domain sequence is presented above the VL domain sequence.
  • the CDRH1-3 and CDRL1-3 are underlined in the 87G7 V H and V L sequences. Highlighted amino acids mark changes in the different regions when compared to the germline sequence of the relevant heavy and light chain variable regions.
  • Heavy and light chain sequences of 87G7, 66B12 and 79A7 are presented above the light chain sequence.
  • mice that are 12-16 weeks old receive an intraperitoneal administration of 10mg of 87G7 or an isotype control mAb at 16 hours pre-infection with 10 5 pfu of live SARS2 virus (WT virus, or UK, SA, BR or India variants).
  • WT virus live SARS2 virus
  • the monoclonal antibody is administered to mice 16 hours before infection with live SARS2 virus. Blood samples are taken at 0, 5 and 10 days post-infection. The mice are monitored daily for weight loss and survival.
  • Figure 18 Virus inoculation and antibody dosing regimen for mouse protection assay
  • ACE2 binding of the S1 B domain - preincubated with serially diluted mAbs 87G7, REGN10933 and REGN10987 - was measured using a ELISA-based method as described in Wang et al. (2020) Nat Commun. 11(1):225.
  • the protein sequences of the CDRs, V H and V L domains, and heavy and light chains (human lgG1 form) of the antibody 87G7, and the DNA sequences of the heavy and light chains of the antibody 87G7 are set out below in ST.25 format.
  • Ala Ala lie Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Vai 50 55 60
  • Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Vai Tyr
  • 87G7 binds strongly to SARS2-S1B and SARS2-Secto (EC50 value of 0.023 g/ml in each case; see Figure 7).
  • 87G7 potently neutralizes viruses pseudotyped with wild-type, E484K mutant, N501Y mutant or K417N mutant SARS2 spike proteins (IC50 values of 8.393 ng/ml, 3.034 ng/ml, 2.144 ng/ml and 0.9476 ng/ml, respectively; see Figure 8).
  • the neutralization of the E484K mutant was more potent than the other 272 anti-SARS2-S antibodies tested in the same assay (see Figure 5).
  • 87G7 also potently neutralizes live SARS2 viruses, including the Wuhan-1 strain, and the UK and South African variants (PRNT50 values of 16.89 ng/ml, 4.875 ng/ml and 8.5 ng/ml, respectively). 87G7 binds to an epitope that is distinct from that bound by REGN 10987, S309, CR3022 and 47D11.
  • the invention provides an anti-SARS2-S antibody that binds to the same epitope as an antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7, and a light chain variable region of the amino acid sequence of SEQ ID NO: 8.
  • the antibody binds to SARS2-S having the sequence of SEQ ID NO: 11 with a KD of 10' 8 M or less (e.g. a KD of 10' 10 M or less), optionally as determined by biolayer interferometry at 25°C.
  • the antibody binds to one or more of the following: (a) SARS2-S having the sequence of SEQ ID NO: 11 ,
  • the antibody binds to:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by SARS2 virus (in a plaque reduction neutralization test), optionally wherein the SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 11.
  • the antibody binds to:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by:
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 11 ,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 15, and
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 16.
  • the antibody :
  • (A) binds to: (a) SARS2-S having the sequence of SEQ ID NO: 11 ,
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by the B.1.1.7 and B.1.351 SARS2 variants.
  • primate cells e.g. VeroE6 cells
  • the antibody binds to:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by:
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 11 ,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 15,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 16, and
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 17.
  • the antibody :
  • SARS2-S having the sequence of SEQ ID NO: 17, and (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by the B.1.1.7, B.1.351 and P.1 SARS2 variants.
  • primate cells e.g. VeroE6 cells
  • the antibody binds to:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by:
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 11 ,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 15,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 16,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 17.
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 58.
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by the B.1.1.7, B.1.351, P.1 and B.1.617.2 SARS2 variants.
  • primate cells e.g. VeroE6 cells
  • the antibody binds to:
  • the antibody :
  • (l) SARS2-S having the sequence of SEQ ID NO: 144, and (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by:
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 11 ,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 15,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 16,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 17.
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 58.
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by the B.1.1.7, B.1.351, P.1 and B.1.617.2 SARS2 variants.
  • primate cells e.g. VeroE6 cells
  • the antibody binds to:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of cells (e.g. Calu-3 cells) (in a plaque reduction neutralization test) by:
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 11 ,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 15,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 16,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 17.
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 58
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 145.
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of cells (e.g. Calu-3 cells) (in a plaque reduction neutralization test) by the B.1.1.7, B.1.351 , P.1 , B.1.617.2 and B.1.1.529 SARS2 variants.
  • cells e.g. Calu-3 cells
  • the invention further provides an anti-SARS2-S antibody that competes for binding to SARS2-S (having the sequence of SEQ ID NO: 11) with an antibody comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7, and a light chain variable region of the amino acid sequence of SEQ ID NO: 8.
  • the anti-SARS2-S antibody does not compete for binding to SARS2-S (having the sequence of SEQ ID NO: 11) with imdevimab.
  • the anti-SARS2-S antibody does not compete for binding to SARS2-S (having the sequence of SEQ ID NO: 11) with a Fab fragment, wherein the heavy chain has the sequence of SEQ ID NO: 20, and the light chain has the sequence of SEQ ID NO: 21.
  • the anti-SARS2-S antibody does not compete for binding to SARS2-S (having the sequence of SEQ ID NO: 11) with a Fab fragment, wherein the heavy chain has the sequence of SEQ ID NO: 22, and the light chain has the sequence of SEQ ID NO: 23. In some embodiments, the anti-SARS2-S antibody does not compete for binding to SARS2-S (having the sequence of SEQ ID NO: 11) with each of the following:
  • the antibody binds to SARS2-S having the sequence of SEQ ID NO: 11 with a K D of 10' 8 M or less, optionally as determined by biolayer interferometry (Forte Bio) at 25°C.
  • the antibody binds to one or more of the following:
  • the antibody binds to:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by SARS2 virus (in a plaque reduction neutralization test), optionally wherein the SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 11.
  • the antibody binds to:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by:
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 11 ,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 15, and
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 16.
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by the B.1.1.7 and B.1.351 SARS2 variants.
  • primate cells e.g. VeroE6 cells
  • the antibody binds to:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by:
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 11 ,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 15,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 16, and
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 17.
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by the B.1.1.7, B.1.351 and P.1 SARS2 variants.
  • primate cells e.g. VeroE6 cells
  • the antibody binds to:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by: (a) vesicular stomatitis virus pseudotyped with SARS2-S having the sequence of SEQ ID NO: 11 ,
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by:
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 11 ,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 15,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 16,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 17.
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 58.
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by the B.1.1.7, B.1.351, P.1 and B.1.617.2 SARS2 variants.
  • primate cells e.g. VeroE6 cells
  • the antibody binds to:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by:
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 11 ,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 15,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 16,
  • SARS2 virus wherein SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 17.
  • SARS2-S of the SARS2 virus has the sequence of SEQ ID NO: 58.
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) (in a plaque reduction neutralization test) by the B.1.1.7, B.1.351, P.1 and B.1.617.2 SARS2 variants.
  • the antibody binds to:
  • the antibody :
  • (B) is capable of neutralizing in vitro infection (e.g. reducing infection by at least 80% relative to an untreated control) of primate cells (e.g. VeroE6 cells) by:

Abstract

L'invention concerne des anticorps qui reconnaissent la protéine de spicule du SARS-CoV-2 (SARS2-S). Dans certains modes de réalisation, les anticorps se lient à SARS2-S avec une affinité élevée et neutralisent puissamment une large gamme de variants de SARS-CoV-2 d'intérêt. Dans certains modes de réalisation, les anticorps fournissent un moyen de prévention, de traitement ou de soulagement d'une infection par SARS2. Dans certains modes de réalisation, les anticorps sont utilisés dans des dosages diagnostiques (par exemple, des dosages sérodiagnostiques pour le SARS2).
PCT/EP2022/075284 2021-09-10 2022-09-12 Anticorps anti-sars2-s WO2023036982A1 (fr)

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GB2112933.3 2021-09-10
GBGB2112933.3A GB202112933D0 (en) 2021-09-10 2021-09-10 Anti-sars2-s antibodies
GBGB2208773.8A GB202208773D0 (en) 2021-09-10 2022-06-15 Anti-SARS2-S antibodies
GB2208773.8 2022-06-15

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