Table Of ContentUS008816058B2
(12) United States Patent (10) Patent N0.: US 8,816,058 B2
Smith et a1. (45) Date of Patent: Aug. 26, 2014
(54) POLYNUCLEOTIDES ENCODING Billard, C., et al., “Switch in the protein tyrosine phosphatase asso
ANTI-CD100 ANTIBODIES OR ciated with human CD100 semaphorin at terminal B-cell differentia
tion stage,” Blood 95(3):965-972, The American Society of Hema
ANTIGEN-BINDING FRAGMENTS THEREOF
tology, United States (2000).
Bleck, G. T., “An Alternative Method for the Rapid Generation of
(75) Inventors: Ernest S. Smith, Ontario, NY (U S);
Stable, High-Expressing Mammalian Cell Lins,” BioProcessing
Terrence Lee Fisher, Rochester, NY Journal 5(4):36-42, International Society for BioProcess Technol
(Us)
ogy, United States (2005).
Bougeret, C., et al., “Increased Surface Expression of a Newly Iden
(73) Assignee: Vaccinex, Inc., Rochester, NY (U S) ti?ed 150-kDa Dimer Early After Human T Lymphocyte Activation,”
TheJournal ofImmunology 148(2):3 18-323, The American Associa
( * ) Notice: Subject to any disclaimer, the term of this tion of Immunologists, United States (1992).
patent is extended or adjusted under 35 Brand, D. D., et a1, “Collagen-induced arthritis,” Nature Protocols
U.S.C. 154(b) by 0 days. 2(5): 1269-1275, Nature Publishing Group, England (2007).
Burgess, W. H., et al., “Possible Dissociation of the Heparin-binding
(21) App1.No.: 13/517,807 and Mitogenic Activities of Heparin-binding (Acidic Fibroblast)
Growth Factor-1 from Its Receptor-binding Activities by Site-di
(22) Filed: Jun. 14, 2012 rected Mutagenesis of a Single Lysine Residue,” The Journal of Cell
Biology 111:2129-2138, The Rockefeller University Press, United
(65) Prior Publication Data States (1990).
Chabbert-De Ponnat, I., et a1, “Soluble CD100 functions on human
US 2012/0270268 A1 Oct. 25, 2012 monocytes and immature dendritic cells require plexin C1 and plexin
B1, respectively,” International Immunology 17(4):439-447, The
Japanese Society for Immunology, Japan (2005).
Related US. Application Data Chen, C., et al., “Generation and Analysis of Random Point Muta
tions in an Antibody CDRZ Sequence: Many Mutated Antibodies
(62) Division of application No. 12/776,187, ?led on May Lose Their Ability to Bind Antigen,” J. Exp. Med. 176:855-866, The
7, 2010, now Pat. No. 8,496,938. Rockefeller University Press, United States (1992).
Claesson-Welsh, L., “Novel paths to blood vessel formation,” Blood
(60) Provisional application No. 61/325,213, ?led on Apr.
105(11):4153-4154, The American Society of Hematology, United
16, 2010, provisional application No. 61/176,826,
States (2005).
?led on May 8, 2009.
Conrotto, P., et al., “Sema4D induces angiogenesis through Met
Recruitment by Plexin B1,” Blood 105(11):4321-4329, The Ameri
(51) Int. Cl. can Society of Hematology, United States (2005).
C07H 21/04 (2006.01) De Pascalis, R., et al., “Grafting 0f ‘Abbreviated’ Complementarity
C12N1/20 (2006.01) Determining Regions Containing Speci?city-Determining Residues
(52) US. Cl. Essential for Ligand Contact to Engineer a Less Immunogenic
Humanized Monoclonal Antibody” The Journal of Immunology
USPC ................................... .. 536/2353; 435/2523
(58) Field of Classi?cation Search 169(6):3076-3084. The American Association of Immunologists,
Inc., United States (2002).
None
Deaglio, S., et al., “CD38 and CD100 lead a network of surface
See application ?le for complete search history.
receptors relaying positive signals for B-CLL growth and survival,”
Blood 105(8):3042-3050, The American Society of Hematology,
(56) References Cited
United States (2005).
U.S. PATENT DOCUMENTS (Continued)
5,070,192 A 12/1991 Earnshaw et a1.
6,576,754 B2 6/2003 Hall et a1.
Primary Examiner * Gerald R Ewoldt
7,351,803 B2 4/2008 Johnson et a1.
7,700,102 B2 4/2010 Hall et a1. (74) Attorney, Agent, or Firm * Thompson Coburn LLP;
7,919,246 B2 4/2011 Lai et a1. Betsy Haanes
7,919,594 B2 4/2011 Smith et a1.
8,067,247 B2 11/2011 Belin et a1.
2010/0285036 A1 11/2010 Smith et a1. (57) ABSTRACT
FOREIGN PATENT DOCUMENTS Isolatedpolynucleotides are provided which encode antibody
VH and VL polypeptides, and anti-CD100 antibodies and
WO 93/14125 A1 7/1993
antigen-binding fragments thereof. In another aspect, the
WO 95/07706 A1 3/1995
WO 97/17368 A1 5/1997 invention provides a vector comprising a polynucleotide of
WO 03/010041 A1 4/2003 the invention. In another aspect, the invention provides a ho st
WO 2004/067034 A1 8/2004 cell comprising the vector of the invention. In another aspect,
WO 2006/110594 A2 10/2006
the invention provides a method of producing an antibody of
OTHER PUBLICATIONS the invention, e.g., for treating diseases associated with
CD100, including certain autoimmune diseases, in?amma
Basile, J. R., et a1, “Semaphorin 4D provides a link between axon tory diseases, and cancers.
guidance processes and tumor-induced angiogenesis,” PNAS
103(24):9017-9022, The National Academy of Sciences of the USA,
United States (2006). 24 Claims, 23 Drawing Sheets
US 8,816,058 B2
Page 2
(56) References Cited Kumanogoh, A., and Kikutani, H., “Immune semaphorins: anew area
of semaphorin research,” Journal of Cell Science 116:3463-3470,
OTHER PUBLICATIONS The Company of Biologists Ltd, England (2003).
Kumanogoh, A., and Kikutani, H., “The CD100-CD72 interaction: a
Delaire, S., et al., “Biological Activity of Soluble CD100. II. Soluble novel mechanism of immune regulation,” TRENDS in Immunology
CD100, Similarly to H-SemaIII, Inhibits Immune Cell Migration,” 22(12):670-676, Elsevier Science Ltd., England (2001).
The Journal ofImmunology 166(7):4348-4354, The American Asso Kumanogoh, A., et al., “Class IV semaphorin Sema4A enhances
ciation of Immunologists, United States (2001). T-Cell activation and interacts with Tim-2,” Nature 419:629-633,
Nature Publishing Group, England (2002).
ElhabaZi, A., et al., “Biological Activity of Soluble CD100. I. The
Extracelluar Region of CD100 is Released from the Surface of T Kumanogoh, A., et al., “Identi?cation of CD72 as a Lymphocyte
Lymphocytes by Regulated Proteolysis,” The Journal ofI mmunology Receptor for the Class IV Semaphorin CD100: a Novel Mechanism
for Regulating B Cell Signaling,” Immunity 13:621-631, Cell Press,
166:4341-4347, The American Association of Immunologists,
United States (2001). United States (2000).
Kumanogoh, A., et al., “Requirement for CD100-CD72 interactions
ElhabaZi, A., et al., “Structure and Function of the Immune
Semaphorin CD100/SEMA4D” Critical ReviewsTM in Immunology, in ?ne-tuning of B-Cell antigen receptor signaling and homeostatic
23(1&2):65-81, Begell House Inc., United States (2003). maintenance of the B-cell compartment,” International Immunology
ElhabaZi, A., et al., “The Human Semaphorin-like Leukocyte Cell 17(10):1277-1282, The Japanese Society for Immunology, Japan
Surface Molecule CD100 Associates with a Serine Kinase Activity,” (2005).
The Journal of Biological Chemistry 272(38):23515-23520, The Kumanogoh, A., et al., “Requirement for the Lymphocyte
American Society for Biochemistry and Molecular Biology, Inc., Semaphorin, CD100, in the Induction of Antigen-Speci?c T Cells
United States (1997). and the Maturation of Dendritic Cells,” The Journal ofI mmunology
Fishwild, D. M., et al., “High-avidity human IgGK monoclonal anti 169(3):1175-1181, The American Association of Immunologists,
bodies from a novel strain of minilocus transgenic mice,” Nature Inc., United States (2002).
Biotechnology 14:845-851,Nature Publishing Group, United States Lamminmaki, U., and Kankare, J. A., “Crystal Structure of a Recom
(1996). binant Anti-estradiol Fab Fragment in Complex with 17B-Estradiol,”
Gauld, S. B., et al., “B Cell Antigen Receptor Signaling: Roles in Cell The Journal of Biological Chemistry 276(39):36687-36694, The
Development and Disease,” Science 296: 1641-1642, The American American Society for Biochemistry and Molecular Biology, Inc.,
Association for the Advancement of Science, United States (2002).
United States (2001).
Giordano, S., et al., “The Semaphorin 4D receptor controls invasive
Lazar, E., et al., “Transforming Growth Factor OLZ Mutation of
growth by coupling with Met,” Nature Cell Biology 4:720-724,
Aspartic Acid 47 and Leucine 48 Results in Different Biological
Nature Publishing Group, England (2002).
Activites,” Molecular and Cellular Biology 8(3): 1247-1252, Ameri
Giraudon, P., et al., “Semaphorin CD100 from Activated T Lympho
cytes Induces Process Extension Collapse in Oligodendrocytes and can Society for Microbiology, United States (1988).
Death of Immature Neural Cells,” The Journal of Immunology, Levin, M. C., et al., “Molecular Mimicry to Neurons Results in
172(2):1246-1255, The American Association of Immunologists, Neurological Disease,” Abstract Viewer and Itinerary Planner: Pro
Inc., United States (2004). gram No. 4153., Society for Neuroscience, United States (2002)
Giraudon, P, et aL, “T-cells in Neuronal Injury and Repair: (Abstract).
Semaphorins and Related T-cell Signals,” NeuroMolecular Medicine Li, D. H., et al., “CD72 Down-Modulates BCR-Induced Signal
7:207-216, Humana Press Inc., United States (2005). Transduction and Diminishes Survival in Primary Mature B Lym
Goldsby, R. A., et al., “Autoimmunity,” in Kuby Immunology 4e: pp. phocytes,” The Journal ofImmunology 176:5321-5328, The Ameri
502-504, W.H. Freeman and Company, United States (2000). can Association of Immunologists, Inc., United States (2006).
Gouttefangeas, C., et al., “Differential proliferative responses in sub Li, D. H-H., et al., “Modulation of Peripheral B Cell Tolerance by
sets of human CD28+ cells delineated by BB27 mAb,” International CD72 in a Murine Model,” Arthritis & Rheumatism 58(10):3192
Immunology 6(3):423-430, The Japanese Society for Immunology, 3904, American College of Rheumatology, United States (2008).
Japan (1993). Moreau-Fauvarque, C. et al., “The Transmembrane Semaphorin
Hall, K. T., et al., “Human CD100, anovel leukocyte semaphorin that Sema4D/CD100, an Inhibitor of Axonal Growth, is Expressed on
promotes B-Cell aggregation and differentiation, ” Proc. Natl. Acad. Oligodendrocytes and Upregulated after CNS Lesion,” The Journal
Sci 93:11780-11785, National Academy of Sciences, United States of Neuroscience 23(27):9229-9239, Society for Neuroscience,
(1996). United States (2003).
Herold, C., et al., “Activation signals are delivered through two Okuno, T., et al., “Roles of Sema4D-Plexin-B1 Interactions in the
distinct epitopes of CD100, a unique 150 kDa human lymphocyte Central Nervous System for Pathogenesis of Experimental Autoim
surface structure previously de?ned by BB18 mAb,” International mune Encephalomyelitis,” The Journal ofI mmunology 184(3): 1499
Immunology 7(1):1-8, The Japanese Society for Immunology, Japan 1506, The American Association of Immunologists, Inc., United
(1994). States (2010).
Herold, C., et al., “CD100 de?nes a newly identi?ed 150-kDa human Pasterkamp, R. J ., “R-Ras ?lls another GAP in semaphorin signal
lymphocyte surface structure,” T-cell antigensipapers T1:50-51 ing,” Trends in Cell Biology 15(2):61-64, Elsevier Ltd, England
(1994). (2005).
Ishida, I., et al., “Involvement of CD100, A lymphocyte semaphorin, Rudikoff, S., et al., “Single amino acid substitution altering antigen
in the activation of the human immune system via CD72: implica binding speci?city,” Proc. Natl. Acad. Sci. USA 79: 1979-1983,
tions for the regulation of immune and in?ammatory responses,” National Academy of Sciences, United States (1982).
International Immunology 15(8):1027-1034, The Japanese Society Shi, W., “The Class IV Semaphorin CD100 Plays Nonredundant
for Immunology (2003). Roles in the Immune System: Defective B and T Cell Activation in
Kikutani, H., and Kumanogoh, A., “Semaphorins in Interactions CD100-De?cient Mice,” Immunity 13:633-642, Cell Press, United
Between T Cells and Antigen-Presenting Cells,” Nature Reviews States (2000).
Immunology 3:159-167, Nature Publishing Group, England (2003). Sierra, J. R. et al., “Tumor angiogenesis and progression are
Kornbluth, et al., “Novel Tyrosine Kinase Identi?ed by enhanced by Sema4D produced by tumor-associated macrophages,”
Phosphotyrosine Antibody Screening of cDNA Libraries,” Molecu J Exp. Med. 205(7):1673-1685, The Rockefeller University Press,
lar and Cellular Biology 8(12):5541-5544, American Society for United States (2008).
Microbiology, United States (1988). Skolnick, J ., and Fetrow, J. S., “From genes to protein structure and
Kruger, R. P., et al., “Semaphorins Command Cells to Move,” Nature function: novel applications of computational approaches in the
Reviews Molecular Cell Biology 6:789-800, Nature Publishing genomic era,” TIBTECH18:34-39, Elsevier Science Ltd., England
Group, England (2005). (2000).
US 8,816,058 B2
Page 3
(56) References Cited immune responses,” Blood 97(11):3498-3504, The American Soci
ety of Hematology, United States (2001).
OTHER PUBLICATIONS Watanabe, C., et al., “Enhanced Immune Responses in Transgenic
Mice Expressing a Truncated Form of the Lymphocyte Semaphorin
Suzuki, K., et al., “Semaphorins and their receptors in immune cell CD100,” TheJournal ofImmunology 167(8):4321-4328, The Ameri
interactions,” Natlmmunology 9(1): 17-23, Nature Publishing Group,
can Association of Immunologists, United States (2001).
England (2008).
Young R. A., and Davis, R. W., “Ef?cient isolation of genes by using
SWiecm, J. M., et al., “ErbB-2 and Met Reciprocally Regulate Cel
lular Signaling via PleXin-Bl,” The Journal of Biological Chemistry antibody probes,” Proc. Natl. Acad. Sci. USA 80: 1194-1 198,
283(4): 1893-1901, The American Society for Biochemistry and National Academy of Sciences, United States (1983).
Molecular Biology, Inc., United States (2008). Zhu, L., et al., “Semaphorin 4D (CD100) is Expressed on the Surface
Tamagnone, L., et al., “PleXins Are a Large Family of Receptors for of Human Platelets and Protrolytically Shed During Platelet Activa
Transmembrane, Secreted, and GPI-Anchored Semaphorins in Ver tion,” Blood 102(11):Poster Session 155-1, The American Society of
tebrates,” Cell 99:71-80, Cell Press, United States (1999). Hematology, United States (2003) (Abstract).
Taniguchi, Y., et al., “Sema4D de?ciency results in an increase in the NCBI EntreZ, GenBank Report, Accession No. X85991, Adams, R.
number of oligodendrocytes in healthy and injured mouse brains,” H., Entry Date Jun. 1995.
Journal of Neuroscience Research 87(13):2833-2841, Wiley-Liss, NCBI EntreZ, GenBank Report, Accession No. AA394007, Wilson,
Inc., United States (2009). R. K, Entry Date Apr. 1997.
Turner, L. J ., and Hall A., “PleXin-Induced Collapse Assay in COS NCBI EntreZ, GenBank Report, Accession No. AA262446,
Cells,” Methods in Enzymology 406:665-676, Elsevier Inc., United Strausberg, R., Entry Date Jan. 1997.
States (2006). Unveri?ed, machine-generated English language translation of the
Voet, D., and Voet, J. G., Biochemistry, pp. 126-128 and 228 French Patent Publication No. FR 2686087 A1 (corresponds to Inter
234,John Wiley & Sons, New York, United States (1990). national Patent Application No. W0 93/ 14 125 A1), European Patent
Wang, X., et al., “Functional soluble CD100/Sema4D released from Of?ce, espacenet databaseiWorldWide (1993) (equivalent of docu
activated lymphocytes: possible role in normal and pathologic ment FPlcited on the accompanying form PTO/SB/08A).
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