IP Library Granted Patent US 12,269,849
Granted Patent B2
US 12,269,849 · App. 18/493,141 · Granted Apr 8, 2025

Factor H binding protein variants and methods of use thereof

Inventor: Peter T. Beernink (Walnut Creek, CA)
Assignee: Children's Hospital & Research Center at Oakland
C07K14/22A61K39/00A61K39/095A61K2039/55505A61K2039/575
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,269,849
App. No.
18/493,141
Granted
Apr 8, 2025
Kind
B2
Abstract

Variant factor H binding proteins that can elicit antibodies that are bactericidal for at least one strain of Neisseria meningitidis , compositions comprising such proteins, and methods of use of such proteins, are provided.

Claims (16)

1. A variant factor H binding protein (fHbp) comprising

an amino acid substitution of the glutamine at amino acid 38 (Q38),

wherein the amino acid substitution at Q38 is Q38R, Q38K, Q38H, Q38F, Q38Y, or Q38W,

wherein the amino acid substitution is relative to the amino acid sequence set forth in SEQ ID NO: 1, and

wherein the variant fHbp comprises an amino acid sequence at least 85% identical to the entire length of the amino acid sequence set forth in SEQ ID NO:1.

2. The variant fHbp of claim 1 , wherein the amino acid substitution at Q38 is Q38R.

3. The variant fHbp of claim 1 , wherein the amino acid sequence of the variant fHbp is at least 90% identical to the entire length of the amino acid sequence set forth in SEQ ID NO:1.

4. The variant fHbp of claim 1 , wherein the amino acid sequence of the variant fHbp is at least 95% identical to the entire length of the amino acid sequence set forth in SEQ ID NO:1.

5. An immunogenic composition comprising:

a) the variant fHbp of claim 1 ; and

b) a pharmaceutically acceptable excipient.

6. The immunogenic composition of claim 5 , wherein the variant fHbp is in a vesicle preparation prepared from a Neisseria meningitidis strain.

7. The immunogenic composition of claim 5 , wherein said pharmaceutically acceptable excipient comprises an adjuvant.

8. The immunogenic composition of claim 7 , wherein the adjuvant is aluminum phosphate or aluminum hydroxide.

9. The immunogenic composition of claim 5 , further comprising Neisserial surface protein A.

10. A method of eliciting an antibody response to Neisseria meningitidis in a human, the method comprising administering to the human an immunologically effective amount of the immunogenic composition of claim 5 .

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 24, 2025
From: CHILDREN'S HOSPITAL & RESEARCH CENTER AT OAKLAND
To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Reel/Frame 070003/0112 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 12, 2023
From: BEERNINK, PETER T.
To: CHILDREN'S HOSPITAL & RESEARCH CENTER AT OAKLAND
Reel/Frame 065845/0032 →
Continuity (6)
Continuation 17065386 · Oct 7, 2020
Continuation 16600259 · Oct 11, 2019
Continuation 16288760 · Feb 28, 2019
Division 15327346
Provisional Application 62028123 · Jul 23, 2014
Related Publication 20240101610A1 · Mar 28, 2024
References Cited (137)
US 7628995B2 · Bos et al. · 2009 [cited by applicant]
US 8101194B2 · Zlotnick et al. · 2012 [cited by applicant]
US 8470340B2 · Beernink et al. · 2013 [cited by applicant]
US 8968748B2 · Granoff et al. · 2015 [cited by applicant]
US 9266942B2 · Granoff et al. · 2016 [cited by applicant]
US 9827300B2 · Beernink et al. · 2017 [cited by applicant]
US 9914756B2 · Beernink · 2018 [cited by applicant]
US 10266572B2 · Beernink et al. · 2019 [cited by applicant]
US 10342860B2 · Beernink et al. · 2019 [cited by applicant]
US 10487122B2 · Beernink · 2019 [cited by applicant]
US 10836799B2 · Beernink · 2020 [cited by applicant]
US 10905754B2 · Beernink et al. · 2021 [cited by applicant]
US 10995122B2 · Beernink · 2021 [cited by applicant]
US 11673920B2 · Beernink · 2023 [cited by applicant]
US 11834476B2 · Beernink · 2023 [cited by applicant]
US 20040167068A1 · Zlotnick et al. · 2004 [cited by applicant]
US 20060127397A1 · Strittmatter · 2006 [cited by applicant]
US 20060171957A1 · Pizza et al. · 2006 [cited by applicant]
US 20060251670A1 · Comanducci et al. · 2006 [cited by applicant]
US 20060257413A1 · Zlotnick et al. · 2006 [cited by applicant]
US 20070026021A1 · Fraser et al. · 2007 [cited by applicant]
US 20080248065A1 · Granoff et al. · 2008 [cited by applicant]
US 20090035328A1 · Granoff et al. · 2009 [cited by applicant]
US 20110256180A1 · Beernink et al. · 2011 [cited by applicant]
US 20110318378A1 · Beernink et al. · 2011 [cited by applicant]
US 20120052092A1 · Exley et al. · 2012 [cited by applicant]
US 20120093852A1 · Anderson · 2012 [cited by examiner]
US 20120107339A1 · Granfoff et al. · 2012 [cited by applicant]
US 20120288517A1 · Beernink et al. · 2012 [cited by applicant]
US 20130022633A1 · Banci et al. · 2013 [cited by applicant]
US 20130149326A1 · Contorni et al. · 2013 [cited by applicant]
US 20130217859A1 · Masignani et al. · 2013 [cited by applicant]
US 20140294886A1 · Pizza · 2014 [cited by applicant]
US 20240025951A1 · Beernink · 2024 [cited by applicant]
AU 2006251283A1 · 2006 [cited by applicant]
AU 2013206190 · 2013 [cited by applicant]
CN 1508253 · 2004 [cited by applicant]
CN 1578785A · 2005 [cited by applicant]
CN 101107007A · 2008 [cited by applicant]
CN 101160412A · 2008 [cited by applicant]
CN 102028941 · 2011 [cited by applicant]
CN 104072590 · 2020 [cited by applicant]
WO WO1999057280 · 1999 [cited by applicant]
WO WO2001052885 · 2001 [cited by applicant]
WO WO2003063766 · 2003 [cited by applicant]
WO WO2004048404 · 2004 [cited by applicant]
WO WO2005102384 · 2005 [cited by applicant]
WO WO2006024954 · 2006 [cited by applicant]
WO WO2006081259 · 2006 [cited by applicant]
WO WO2007060548 · 2007 [cited by applicant]
WO WO2009038889 · 2009 [cited by applicant]
WO WO2009104097 · 2009 [cited by applicant]
WO WO2009114485 · 2009 [cited by applicant]
WO WO2010027872 · 2010 [cited by applicant]
WO WO2010028096 · 2010 [cited by applicant]
WO WO2010028859 · 2010 [cited by applicant]
WO WO2010046715 · 2010 [cited by applicant]
WO WO2010127172 · 2010 [cited by applicant]
WO WO2011051893 · 2011 [cited by applicant]
WO WO2011126863 · 2011 [cited by applicant]
WO WO2013006055 · 2013 [cited by applicant]
WO WO2013078223 · 2013 [cited by applicant]
WO WO2013132452A2 · 2013 [cited by applicant]
WO WO2014030003 · 2014 [cited by applicant]
WO WO2015128480 · 2015 [cited by applicant]
WO WO2015170875 · 2015 [cited by applicant]
WO WO2016008960 · 2016 [cited by applicant]
Anez et al. (2009) “Passage of dengue virus type 4 vaccine candidates in fetal rhesus lung cells selects heparin-sensitive variants that result in loss of infectivity and immunogenicity in rhesus macaques” Journal of vi… [cited by applicant]
Beernink et al.(2010) “Impaired immunogenicity of a meningococcal factor H-binding protein vaccine engineered to eliminate factor h binding” [cited by applicant]
Beernink et al. (2011) “A Meningococcal Factor H Binding Protein Mutant That Eliminates Factor H Binding Enhances Protective Antibody Responses to Vaccination” The Journal of Immunology, 186(6):3606-3614. [cited by applicant]
Beernink, P.T., et al., Abstracts of 16 [cited by applicant]
Beernink et al. In: Program and Abstract Guide, 17th International Pathogenic Neisseria Conference, Banff, Alberta, Canada, p. 58, #OM42, Sep. 11-16, 2010. [cited by applicant]
Beernink, et al.(2006) “Rapid Genetic Grouping of Factor h-binding Protein (Genome-Derived neisserial antigen 1870), a Promising Group B Meningoccal Vaccine Candidate”, [cited by applicant]
Beernink, et al., “A Region of the N-Terminal Domain of Meningococcal Factor H-Binding Protein that Elicits Bactericidal Antibody Across Antigenic Variant Groups”, Molecular Immunology, 2009, 46(8-9):1647-1653. [cited by applicant]
Beernink, et al., “Fine Antigenic Specificity and Cooperative Bactericidal Activity of Monoclonal Antibodies Directed at the Meningococcal Vaccine Candidate Factor H-Binding Protein”, Infection and Immunity, 2008, 76(9)… [cited by applicant]
Beernink, et al., “Prevalence of Factor H-Binding Protein Variants and NadA Among Meningococcal Group B Isolates from the United States: Implications for the Development of a Multicomponent Group B Vaccine”, Journal of … [cited by applicant]
Beernink, et al., The Modular Architecture of Meningococcal Factor H-Binging Protein, Microbiology, 2009, 155:2873-2883. [cited by applicant]
Beernink, et al., Factor H Binding Protein. GenBank Direct Submission Accession ACJ45782 [online]. Nov. 23, 2009 [retrieved on Aug. 2, 2011], retrieved from the Internet: URL:http://www.ncbi.nlm.nih.gov/proteinacj45782,… [cited by applicant]
Beernink et al., “Bactericidal Antibody Responses Induced by Meningococcal Recombinant Chimeric Factor H-Binding Protein Vaccines”, Infection and Immunity, 2008, 76(6):2568-2575. [cited by applicant]
Borrow et al., “Serological Basis for Use of Meningococcal Serogroup C Conjugate Vaccines in the United Kingdom: Reevaluation of Correlates of Protection”, Infect. Immun. (2001) 69(3):1568-1573. [cited by applicant]
Davila et al. (2010) “Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease” [cited by applicant]
De Filippis, et al., Factor H Binding Protein. Gen Bank Direct Submission Accession ACZ93150 [online]. Dec. 15, 2009 [retrieved on Aug. 2, 2011], retrieved from the internet: URL:http://www.ncbi.nlm.nih.gov/protein/acz9… [cited by applicant]
De Filippis, et al., Factor H Binding Protein. GenBank Direct Submission Accession ACZ93290 [online]. Dec. 15, 2009] retrieved on Aug. 2, 2011], retrieved from the Internet: URL:http://www.ncbi.nlm.nih.gov/protein/acz93… [cited by applicant]
Dunphy, et al., “Effect of Factor H-Binding Protein Sequence Variation on Factor H Binding and Survival of [cited by applicant]
Fletcher, et al. (2004) “Vaccine potential of the Neisseria meningitidis 2086 lipoprotein” [cited by applicant]
Fukasawa, et al., Immune Response to Naitive NadA from Neisseria Meningitidis and its Expression in Clinical Isolates in Mrazil, Journal of Medical Microbiology, 2003, 52:121-125. [cited by applicant]
Genbank Accession No. AAW88802, Factor H binding protein from [cited by applicant]
Genbank Accession No. AGA84509.1, Factor H binding protein from [cited by applicant]
GenBank Accession No. AY548370 “Neisseria meningitidis strain H44/76 lipoprotein (gna1870) gene, complete cds” (AAT01289.1) (from N. meningitidis strain H44/76), dated May 1, 2004. [cited by applicant]
GenBank Accession No. AY548371 “Neisseria meningitidis strain CU385 lipoprotein (gna1870) gene, complete cd” (AAT01290.1) (from N. meningitidis strain CU385), dated May 1, 2004. [cited by applicant]
GenBank Accession No. AY548372 “Neisseria meningitidis strain BZ83 lipoprotein GNA1870 (gna1870) gene, complete cd” (AAS56915.1) (from N. meningitidis strain BZ83), dated Apr. 22, 2004. [cited by applicant]
GenBank Accession No. AY548373 “Neisseria meningitidis strain 4243 lipoprotein GNA1870 (gna1870) gene, complete cd” (AAS56916.1) (from N. meningitidis strain 4243), dated Apr. 22, 2004. [cited by applicant]
GenBank Accession No. AY548374 “Neisseria meningitidis strain M6190 lipoprotein GNA1870 (gna1870) gene, complete cd” (AAS56917.1) (from N. meningitidis strain M6190), dated Apr. 22, 2004. [cited by applicant]
GenBank Accession No. AY548375 “Neisseria meningitidis strain N98/254 lipoprotein GNA1870 (gna1870) gene, complete cd” (AAS56918.1) (from N. meningitidis strain NZ98/254), dated Apr. 22, 2004. [cited by applicant]
GenBank Accession No. AY548376 “Neisseria meningitidis strain M1390 lipoprotein GNA1870 (gna1870) gene, complete cds” (AAS56919.1) (from N. meningitidis strain M1390), dated Apr. 22, 2004. [cited by applicant]
GenBank Accession No. AY548377 “Neisseria meningitidis strain M4105 lipoprotein GNA1870 (gna1870) gene, complete cd” (AAS56920.1) (fHbp ID 4 from N. meningitidis strain M4105), dated Apr. 22, 2004. [cited by applicant]
GenBank Accession No. NC_003112, “Neisseria meningitidis MC58, complete genom” GeneID: 904318 (NCBI Ref. NP_274866), fHbp ID 1 from N. meningitidis strain MC58, ), dated May 24, 2010. [cited by applicant]
GenBank Accession No. NP_000177 (P08603), and its encoding nucleic acid as NM_000186, “complement factor H isoform a precursor [ [cited by applicant]
Giuliani, et al. (2005) “The region comprising amino acids 100 to 255 of Neisseria meningitidis lipoprotein GNA 1870 elicits bactericidal antibodies” [cited by applicant]
Goldschneider, et al. (1969) “Human Immunity to the Meningococcus: I. The Role of the Humoral Antibodies” [cited by applicant]
Granoff, et al. (1998) “Bacterial Monoclonal Antibodies That Define Unique Meningococcal B Polysaccharide Epitopes That Do Not Cross-React with Human Polysialic Acid” [cited by applicant]
Granoff, et al. (2009) “Binding of complement factor H (fH) to Neisseria meningitidis is specific for human fH and inhibits complement activation by rat and rabbit sera” [cited by applicant]
Huo et al. (2005) “Protective antibody responses elicited by a meningococcal outer membrane vesicle vaccine with overexpressed genome-derived neisserial antigen 1870” Journal of Infectious Diseases; 192(4):580-590. [cited by applicant]
Johnson S. et al., “Design and Evaluation of Meningococcal Vaccines through Structure-Based Modification of Host and Pathogen Molecules”, PLOS Pathogens (2012) 8(10): e1002981. [cited by applicant]
Konar et al. (2015) “A Mutant Library Approach to Identify Improved Meningococcal Factor H Binding Protein Vaccine Antigens” PLoS One. 10(6):e0128185. [cited by applicant]
Lazar et al. (1988) “Transforming Growth Factor alpha: Mutation of Aspartic Acid 47 and Leucine 48 Results in Different Biological Activities” Cellular Biol. 8(3):1247-1252. [cited by applicant]
Lewis, et al., The Meningococcal Vaccine Candidate Neisserial Surface Protein A (NspA) Binds to Factor H and Enhances Meningococcal Resistance to Complement, PLOS Pathogens, 2010, 6(7):1-20. [cited by applicant]
Madico, et al., “The Meningococcal Vaccine Candidate GNA1870 Binds the Complement Regulatory Protein Factor H and Enhances Serum Resistance”, 2006, The Journal of Immunology, 177:501-510. [cited by applicant]
Madico, et al., Factor H Binding Protein. GenBank Direct Submission Accession ABC59063 [online], Jun. 20, 2006 [retrieved on Aug. 2, 2011], retrieved from the Internet: URL:http://www.ncbi.nlm.nih.gov/protein/abc59063, … [cited by applicant]
Mascioni et al. (2009) “Structural Basis for the Immunogenic Properties of the Meningococcal Vaccine Candidate LP2086” Journal of Bio. Chem.; 284(13):8738-8746. [cited by applicant]
Masignani, et al., “Vaccination against Neisseria meningitides Using Three Variants of the Lipoprotein GNA1879,” Journal Exp. Med., 2003, 197(6):789-799. [cited by applicant]
Maslanka, et al., “Standardization and a Multilaboratory Comparison of Neisseria Meningitidis Serogroup A and C Serum Bactericidal Assays”, Clinical Diagnostic Laboratory Immunology, 1997, 4(2):156-157. [cited by applicant]
McDowell, et al., “Demonstration of the Involvement of Outer Surface Protein E Coiled Coil Structure and Higher Order Structural Elements in the Binding of Infection-Induced Antibody and the Complement-Regulatory Protei… [cited by applicant]
Morrison, K.L., et al., “Combination alanine-scanning,” Curr. Opin. Chem. Biol. (2001) 5:302.307. [cited by applicant]
Murphy, et al., Factor H Binding Protein Variant A72_001. GenBank Direct Submission Accession ACI46937 [online]. Aug. 4, 2009 [retrieved from the internet]:URL:http://www.ncbi.nim.nih.gov/protein/aci46937, p. 1. [cited by applicant]
Murphy, et al., “Sequence Diversity of the Factor H Binding Protein Vaccine Candidate in Epidemiologically Relevant Strains of Serogroup B Neisseria meningitidis”, The Journal of Infectious Diseases, 2009, pp. 379-389. [cited by applicant]
Ngampasutadol et al., “A Novel Interaction Between Factor H SCR 6 and the Meningococcal Vaccine Candidate GNA 1870: Implications for Meningococcal Pathogenesis and Vaccine Development”, Molecular Immunology, 2007, 44(1-… [cited by applicant]
Ngampasutadol et al., “Human Factor H Interacts Selectively with Neisseria Gonorrhoeae and Results in Species-Specific Complement Evasion”, The Journal of Immunology, 2008, 180(5):3426-3435. [cited by applicant]
Pajon, et al. “Design of meningococcal factor H binding protein mutant vaccines that do not bind human complement factor H”, Infect Immun. (2012) 80(8):2667-77. [cited by applicant]
Pajon, et al. (2010) “Frequency of factor H-binding protein modular groups and susceptibility to cross-reactive bactericidal activity in invasive meningococcal isolates” Vaccine 28(9):2122-2129. [cited by applicant]
Scarselli, et al. (2009) “Epitope mapping of a bactericidal monoclonal antibody against the factor H binding protein of Neisseria meningitidis” [cited by applicant]
Schneider, et al. “Supplemental Methods for Neisseria Meningitides Recruits Factor H Using Protein Mimicry of Host Carbohydrates”, Nature, 2009, 1-17. [cited by applicant]
Schneider, et al. “Neisseria Meningitides Recruits Factor H Using Protein Mimicry of Host Carbohydrates”, Nature, 2009, 458:890-895. [cited by applicant]
Seib, et al., “Characterization of Diverse Subvariants of the Meningococcal Factor H (fH) Binding Protein for Their Ability to Bind fH, to Mediate Serum Resistance, and to Induce Bactericidal Antibodies”, 2011, Infectio… [cited by applicant]
Shaughnessy, et al. (2009) “Functional comparison of the binding of factor H short consensus repeat 6 (SCR 6) to factor H binding protein from Neisseria meningitidis and the binding of factor H SCR 18 to 20 to Neisseria… [cited by applicant]
Skolnick et al. (2000) “From genes to protein structure and function: novel applications of computational approaches in the genomic era” Trends in Biotechnology. 18:34-39. [cited by applicant]
Skowronski et al. (2014) “Low 2012-13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses” PloS one, 9(3):e92153. [cited by applicant]
Tettelin, et al., Uniprot Q9JXV4 [online] Oct. 1, 2000 [retrieved on Aug. 2, 2011], retrieved from the internet: URL:http://www.uniprot.org/uniprot/Q9JXV4.txt, p. 1. [cited by applicant]
Vu et al., “A Broadly Cross-Reactive Monoclonal Antibody Against an Epitope on the N-terminus of Meningococcal fHbp”, Scientic Reports (2012) 2(341):1-8. [cited by applicant]
Welsch, et al., Complement-Dependent Synergistic Bactericidal Activity of Antibodies Against Factor H-Binding Protein, a Sparsely Distributed Meningococcal Vaccine Antigen, The Journal of Infectious Disease, 2008, 197:1… [cited by applicant]
Welsch, et al., “Protective Activity of Monoclonal Antibodies to Genome-Derived Neisserial Antigen 1870, a Neisseria Meningitidis Candidate Vaccine”, Journal of Immunology, 2004, 172:5606-5615. [cited by applicant]
Welsch, et al., Lipoprotein GNA1870. GenBank Direct Submission Accession AAS56918 [online], Apr. 22, 2004 [retrieved on Aug. 2, 2011], retrieved from the Internet:<URL:http://www.ncbi.nlm.nih.gov/protein/AAS56918, p. 1. [cited by applicant]
GENBANK “Factor H binding protein”, Accession No. AGA84494.1, 2012, 5 pages. [cited by applicant]
Greenspan et al., “Defining epitopes: It's not as easy as it seems”, Commentary Structural Analysis Nature Biotechnology, 1999, 17:936-937. [cited by applicant]
McGuinness et al., “Class 1 outer membrane protein of Neisseria meningitidis: epitope analysis of the antigenic diversity between strains, implications for subtype definition and molecular epidemiology”, Molecular Micro… [cited by applicant]
McGuinness et al., “Point mutation in meningococcal por A gene associated with increased endemic disease”, The Lancet, Mar. 2, 1991, 337:514-517. [cited by applicant]
Rudinger “Characteristics of the amino acids as components of a peptide hormone sequence”, University Park Press, 1976, 1-7. [cited by applicant]