Granted Patent
B2
US 12,606,937 · App. 18/054,045 · Granted Apr 21, 2026
Humanized antibodies with ultralong complementary determining regions
Assignee:
TAURUS BIOSCIENCES, LLC
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Abstract
The present disclosure provides humanized antibodies, including antibodies comprising an ultralong CDR3 and uses thereof.
Claims (19)
1 . An antibody comprising:
(a) a modified heavy chain variable domain comprising, in order:
(i) a FR1-CDR1-FR2-CDR2-FR3 region comprising the FR1, FR2 and FR3 of the human germline VH4-34 variable domain (SEQ ID NO: 33) with the exception of at least one amino acid substitution selected from Q5R, Q6E, and E50S, and up to 5 additional amino acids substitutions at positions other than positions 5, 6, and 50;
(ii) an ultralong CDR3 that is at least 35 amino acids in length; and
(iii) a framework region 4 (FR4); and
(b) a light chain variable domain.
2 . The antibody of claim 1 , wherein the SEQ ID NO: 33 comprises at least two amino acid substitution selected from Q5R, Q6E, and E50S.
3 . The antibody of claim 1 , wherein the SEQ ID NO: 33 comprises three amino acid substitution selected from Q5R, Q6E, and E50S.
4 . The antibody of claim 1 , wherein the light chain variable domain is a VL1-51 light chain variable domain or a variant thereof.
5 . The antibody of claim 4 , wherein the light chain variable domain comprises the amino acid sequence of residues 1-90 of SEQ ID NO: 37 with the exception of one or more amino acid substitutions at positions corresponding to positions 2, 5, 8, 12, 13, 14, 46, 47, 51, 52, and 53 in SEQ ID NO: 37.
6 . The antibody of claim 5 , wherein the amino acid substitutions are selected from S2A, T5N, P8S, A12G, A13S, P14L, K46R, L47T, D51G, N52D, and N53T.
7 . The antibody of claim 5 , wherein the light chain variable region comprises at least two of the amino acid substitutions.
8 . The antibody of claim 1 , wherein the FR4 comprises an amino acid sequence selected from the group consisting of:
(i) WGHGTAVTVSS (SEQ ID NO: 570),
(ii) WGKGTTVTVSS (SEQ ID NO: 571),
(iii) WGRGTLVTVSS (SEQ ID NO: 573), and
(iv) WGQGLLVTVSS (SEQ ID NO: 500).
9 . The antibody of claim 1 , wherein antibody is a single-chain variable fragment.
10 . The antibody of claim 1 , wherein heavy and light chain variable domains are on different polypeptides.
Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 10, 2022
From: BAZIRGAN, OMAR; DE LOS RIOS, MIGUEL
To: FABRUS, INC.
Reel/Frame 061725/0824 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 10, 2022
From: FABRUS, INC.
To: TAURUS BIOSCIENCES, INC.
Reel/Frame 061917/0952 →
CHANGE OF NAME
Recorded Nov 10, 2022
From: TAURUS BIOSCIENCES, INC.
To: TAURUS BIOSCIENCES, LLC
Reel/Frame 061917/0986 →
Continuity (4)
Continuation
14905765
Provisional Application
61856010
· Jul 18, 2013
References Cited (107)
US 5877293A
· Adair et al.
· 1999
[cited by applicant]
US 6740747B2
· Kaushik et al.
· 2004
[cited by applicant]
US 7196185B2
· Kaushik et al.
· 2007
[cited by applicant]
US 7575893B2
· Simmons
· 2009
[cited by applicant]
US 7592010B2
· Rosen et al.
· 2009
[cited by applicant]
US 9221902B2
· Smider et al.
· 2015
[cited by applicant]
US 9403904B2
· Smider et al.
· 2016
[cited by applicant]
US 9644021B2
· Wang et al.
· 2017
[cited by applicant]
US 20030170646A1
· Kaushik et al.
· 2003
[cited by applicant]
US 20110293513A1
· Govindan et al.
· 2011
[cited by applicant]
US 20120316071A1
· Smider et al.
· 2012
[cited by applicant]
US 20140050720A1
· Smider et al.
· 2014
[cited by applicant]
US 20150011431A1
· Smider et al.
· 2015
[cited by applicant]
US 20160168231A1
· De Los Rios et al.
· 2016
[cited by applicant]
US 20160237156A1
· Wang et al.
· 2016
[cited by applicant]
CN 1656121A
· 2005
[cited by applicant]
JP 2005522197
· 2005
[cited by applicant]
WO WO9320210A1
· 1993
[cited by applicant]
WO WO199320210
· 1993
[cited by applicant]
WO WO1994018221
· 1994
[cited by applicant]
WO WO2002022809
· 2002
[cited by applicant]
WO WO2003030821
· 2003
[cited by applicant]
WO WO2003085086
· 2003
[cited by applicant]
WO WO2005056759
· 2005
[cited by applicant]
WO WO2010028791
· 2010
[cited by applicant]
WO WO2010054007
· 2010
[cited by applicant]
WO WO2010054010
· 2010
[cited by applicant]
WO WO2011044542
· 2011
[cited by applicant]
WO WO2011056997
· 2011
[cited by applicant]
WO WO2012170977
· 2012
[cited by applicant]
WO WO2013106485
· 2013
[cited by applicant]
WO WO2013106489
· 2013
[cited by applicant]
WO WO2014110368
· 2014
[cited by applicant]
WO WO2015010100
· 2015
[cited by applicant]
WO WO2015017146
· 2015
[cited by applicant]
U.S. Appl. No. 14/946,445, filed Nov. 19, 2015, Smider et al.
[cited by applicant]
U.S. Appl. No. 15/140,175, filed Apr. 27, 2016, Smider et al.
[cited by applicant]
Baker, P.J., “The pain of “chronic Lyme disease”: moving the discourse in a different direction,” The FASEB Journal, 26(1):11-12 (2012).
[cited by applicant]
Brumeanu et al., “Efficient loading of identical viral peptide onto class II molecules by antigenized immunoglobulin and influenza virus,” J. Exp. Med 178(5):1795-1799 (1993).
[cited by applicant]
Casset et al., “A peptide mimetic of an anti-CD4 monoclonal antibody by rational design,” BBRC 307(1):198-205 (2003).
[cited by applicant]
Chen et al., “Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen,” J. Mol. Bio. 293(4): 865-881 (1999).
[cited by applicant]
Haakenson et al., “Diversity in the cow Ultralong CDR H3 Antibody repertoire,” Frontiers in Immunology (2018) 9:1262.
[cited by applicant]
Hosseini et al., “Duplicated copies of the bovine JH locus contribute to the Ig repertoire,” Int. Immunol. (2004) 16(6):843-852.
[cited by applicant]
Hust et al., “Single chain Fab (scFab) fragment,” BMC Biotechnology (2007) 7:14.
[cited by applicant]
Inoue et al., “Affinity transfer to a human protein by CDR3 grafting of camelid VHH,” Protein Science. 20(12):1971-1981 (2011).
[cited by applicant]
Lefranc et al., “IMGT, the international ImMunoGeneTics information system.” Nucleic Acids Res. Jan. 2009;37(Database issue):D1006-12.
[cited by applicant]
Muyldermans et al., “Distinct Antibody Species: Structural Differences Creating Therapeutic Opportunities,” Curr Opin Immunol. Jun. 2016 ; 40: 7-13.
[cited by applicant]
NCBI, GenBank accession No. DM113215.1 (Jun. 18, 2009).
[cited by applicant]
Nuttal et al., “Selection and affinity maturation of IgNAR variable domains targeting Plasmodium falciparum AMA1,” Proteins: Structure, Function. and Bioinformatics. 55(1):187-197 (2004).
[cited by applicant]
Pistillo et al., “Molecular Characterization and Applications of Recombinant SCFV Antibodies to CD152 Co-Stimulatory Molecule,” Tissue Antigens 55(3):229-238.
[cited by applicant]
Qin et al., “Fusion protein of CDR mimetic peptide with Fc inhibit TNF-alpha induced cytotoxicity,” Molecular Immunology 43(6):660-666.
[cited by applicant]
Qiu et al. “Small antibody mimetics comprising two complementarity determining regions and a framework region for tumor targeting,” Nature Biotechnology 25(8):921-929 (2007).
[cited by applicant]
Rader et al., “The rabbit antibody repertoire as a novel source for the generation of therapeutic human antibodies,” Journal of Biological Chemistry. 275:13668-13676 (2000).
[cited by applicant]
Ramsland et al., “Incorporation of long CDR3s into V domains: implications for the structural evolution of the antibody combining site,” Experimental and Clinical Immunogenetics. 18(4):176-198 (2001).
[cited by applicant]
Roche et al., “Invited review: Body condition score and its association with dairy cow productivity, health, and welfare,” J. Dairy Sci., 92(12):5769-5801 (2009).
[cited by applicant]
Sain et al., “Bovine IgM antibodies with exceptionally long complementarity-determining region 3 of the heavy chain share unique structural properties conferring restricted VH + Vlambda pairings,” international immunolo…
[cited by applicant]
Simmons et al., “Shark IgNAR antibody mimotopes target a murine immunoglobulin through extended CDR3 loop structures,” Proteins: Structure, Function, and Bioinformatics. 71(1): 119-130 (2008).
[cited by applicant]
Sok et al., “Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows,” Nature. Aug. 3, 2017; 548(7665): 108-111.
[cited by applicant]
Streltsov et al., “Crystal Structure of the Amyloid-p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease,” Journal of Neuroscience. 31(4) 1419-1426 (2011).
[cited by applicant]
Streltsov et al., “Supplemental Material Crystal Structure of the Amyloid-p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease,” (2011) Journal of Neuroscience. 31(4) 1419-1426 (2011).
[cited by applicant]
Wells “Additivity of Mutational Effects in Proteins,” Biochemistry 29:8509-8517 (1990).
[cited by applicant]
Wold et al., “Antibody Therapeutics in Oncology,” Immunotherapy (Los Angel). Mar. 2016 ; 2(1):pii:108.
[cited by applicant]
Wynne et al., “Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial,” International Journal of Obesity 30(12) ⋅ 1729-1736 (2006…
[cited by applicant]
Yang et al., “The three complementarity-determining region-like loops in the second extracellular domain of human Fc alpha/mu receptor contribute to its binding of IgA and IgM,” Immunobiology 218(5):798-809 (2013).
[cited by applicant]
Zhao et al., “The bovine antibody repertoire,” Developmental and Comparative Immunology. 30⋅ 175-186 (2006).
[cited by applicant]
Saini et al., “Exceptionally long CDR3H region with multiple cysteine residues in functional bovine IgM antibodies,” European Journal of Immunology, (1999) 29(8): 2420-2426.
[cited by applicant]
Smider, “Cow Antibodies: A New Structural Class of Antibody Using Ultralong CDR3s,” World ADC, Oct. 16, 2013. Retrieved from http://adc-summit.com/uploads/files/2463_ADC_/Vaughn_Smider.pdf.
[cited by applicant]
Stanfield et al., “Conservation and diversity in the ultralong third heavy-chain complementarity-determining region of bovine antibodies,” Science Immunology (2016) 1:aaf7962.
[cited by applicant]
Wang et al., “Reshaping Antibody Diversity,” Cell (2013) 153(6):1379-1393.
[cited by applicant]
Zhang et al., “An Antibody CDR3-Erythropoietin Fusion Protein,” ACS Chem Biol (2013) 8(10):2117-2121.
[cited by applicant]
Zhang et al., “Functional Antibody CDR3 Fusion Proteins with Enhanced Pharmacological Properties,” Angew Chem Int Ed Engl (2013) 52(32):8295-8298.
[cited by applicant]
Zhang et al., “Rational Design of humanized dual-agonist antibodies,” Journal of the American Chemical Society (2015) 137(1):38-41.
[cited by applicant]
U.S. Appl. No. 15/660,852, filed Jul. 26, 2017, by Smider et al.
[cited by applicant]
Koti et al., “Novel atypical nucleotide insertions specifically at VH-DH junction generate exceptionally long CDR3H in cattle antibodies”, Molecular Immunology, 2010, 47(11-12): 2119-2128.
[cited by applicant]
Saini et al., “Exceptionally long CDR3H region with multiple cysteine residues in functional bovine IgM antibodies”, Eur. J. Immunol., 1999, 29: 2420-2426.
[cited by applicant]
Almagro et al., “Humanization of antibodies”, Frontiers in Bioscience, 2008; 1(13): 1619-1633.
[cited by applicant]
De Genst et al., “Antibody repertoire development in camelids”, Developmental and Comparative Immunology, 2006; 30: 187-198.
[cited by applicant]
Ward et al., “Binding activities of a repertoire of single immunoglobulin variable domains secreted from
[cited by applicant]
Barthelemy et al., “Comprehensive analysis of the factors contributing to the stability and solubility of autonomous human VH domains”, Journal of Biological Chemistry, 2008; 283(6): 3639-3654.
[cited by applicant]
Choi et al., “Predicting antibody complementarity determining region structures without classification”, 2011, Molecular BioSystems, 2011; 7: 3327-3334.
[cited by applicant]
Griffiths et al., “Human anti-self antibodies with high specificity from phage display libraries.”, The European Molecular Biology Organization Journal, 1993; 12(2): 725-734.
[cited by applicant]
Klimka et al., “Human anti-CD30 recombinant antibodies by guided phage antibody selection using cell panning”, British Journal of Cancer, 2000; 83(2): 252-260.
[cited by applicant]
Beiboer et al., “Guided selection of a pan carcinoma specific antibody reveals similar binding characteristics yet structural divergence between the original murine antibody and its human equivalent”, Journal of Molecul…
[cited by applicant]
Ottensmeier et al., “Isotype switch variants reveal clonally related subpopulations in diffuse large B-cell lymphoma”, Blood, 2000; 96(7): 2550-2556.
[cited by applicant]
Pistillo et al., “Molecular Characterization and Applications of Recombinant SCFV Antibodies to CD152 Co-Stimulatory Molecule”, Tissue Antigens, Mar. 2000, 55(3): 229-238.
[cited by applicant]
Qin et al., “Fusion protein of CDR mimetic peptide with Fc inhibit TNF-alpha induced cytotoxicity”, Molecular Immunology, Feb. 2006, 43(6): 660-666.
[cited by applicant]