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Patent No.: US 8877913 B2 USOO8877913B2 (12) United States Patent (10) Patent No.: US 8,877,913 B2 Nakagawa et a1. (45) Date of Patent: Nov. 4, 2014 (54) ANTI-CD4 ANTIBODY OTHER PUBLICATIONS (71) Applicants:Tomoaki Nakagawa, Tokyo (JP); Darrell Anderson et al., “A Primatized MAb to Human CD4 Causes Sayaka Hori, Tokyo (JP); Rinpei Niwa, Receptor Modulation, without Marked Reduction in CD4+T Cells in Tokyo (JP); Tsuguo Kubota, Tokyo (JP); Chimpanzees: In Vitro and in Vivo Characterization of a MAb Kazuhiro Masuda, Tokyo (JP); (IDEC-CE9.1) to Human CD4”, Clinical Immunology and Kazuyasu Nakamura, Tokyo (JP) Immunopathology, 1997, 84(1): 73-84. Paul J. Carter, “Potent antibody therapeutics by design”, Nature (72) Inventors: Tomoaki Nakagawa, Tokyo (JP); Reviews, Immunology, 2006, 6: 343-357. Sayaka Hori, Tokyo (JP); Rinpei Niwa, Youn Kim et al., “Clinical ef?cacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma”, Tokyo (JP); Tsuguo Kubota, Tokyo (JP); Blood, 2007, 109: 4655-4662. Kazuhiro Masuda, Tokyo (JP); Onn M. Kon et al., “Randomised, dose-ranging, placebo-controlled Kazuyasu Nakamura, Tokyo (JP) study of chimeric antibody to CD4 (keliximab) in chronic severe asthma”, The Lancet, 1998, 352: 1109-1113. (73) Assignee: Kyowa Hakko Kirin Co., Ltd, Tokyo Matthias Merkenschlarger et al., “Functional Epitope Analysis of the (J P) Human CD4 Molecule: The MHC Class II-Dependent Activation of Resting T Cells is Inhibited by Monoclonal Antibodies to CD4 Notice: Subject to any disclaimer, the term of this Regardless whether or Not They Recognize Epitopes Involved in the patent is extended or adjusted under 35 Binding of MHC Class II or HIV gp120”, The Journal of Immunol U.S.C. 154(b) by 86 days. ogy, 1990, 145(9): 2839-2845. Akito Natsume et al., “Engineered Antibodies 0f IgGl/IgG3 Mixed (21) Appl. No.: 13/755,472 Isotype with Enhanced Cytotoxic Activities”, Cancer Research, 2008,68: 3863-3872. Roland Newman et al., “‘Primatization’” of recombinant antibodies (22) Filed: Jan. 31, 2013 for immunotherapy of human diseases: A macaque/human chimeric antibody against human CD4, Biotechnology, 1992, 10: 1455-1460. (65) Prior Publication Data Govind Ragupathi et al., “Antibodies against Tumor Cell Glycolipids and Proteins, but Not Mucins, Mediate Complement-Dependent US 2013/0177944 A1 Jul. 11,2013 Cytotoxicity”, The Journal of Immunology, 2005, 174: 5706-5712. Manjula P. Reddy et al., “Elimination of Fe Receptor-Dependent Effector Functions of a Modi?ed IgG4 Monoclonal Antibody to Related US. Application Data Human CD4”, The Journal of Immunology, 2000, 164: 1925-1933. Ellis L. Reinherz et al., “Separation of functional subsets of human T (62) Division of application No. 12/647,698, ?led on Dec. cells by amonoclonal antibody”, Immunology, Proc. Natl. Acad. Sci. 28, 2009, now Pat. No. 8,399,621. USA, 1979, 76(8): 4061-4065. David Rider et al., “A Human CD4 Monoclonal Antibody for the (60) Provisional application No. 61/141,393, ?led on Dec. Treatment of T-Cell Lymphoma Combines Inhibition of T-Cell Sig 30, 2008. naling by a Dual Mechanism with Potent Fc-Dependent Effector Activity”, Cancer Research, 2007, 67(20): 9945-9953. (30) Foreign Application Priority Data (Continued) Dec. 26, 2008 (JP) ............................... .. 2008-331904 Primary Examiner * Laura B Goddard Assistant Examiner * Meera Natarajan (51) Int. Cl. (74) Attorney, Agent, or Firm * Sughrue Mion, PLLC C07H 21/04 (2006.01) (52) US. Cl. (57) ABSTRACT USPC ................................... .. 536/2353; 530/387.1 An anti-CD4 antibody which binds to CD4, has a high a?inity Field of Classi?cation Search (58) and has a high effector activity, such as an antibody-depen None dent cellular cytotoxicity (ADCC activity) or complement See application ?le for complete search history. dependent cellular cytotoxicity (CDC activity), is required for a disease relating to a CD4-expressing cell. (56) References Cited The present invention can provide a monoclonal antibody or an antibody fragment thereof, which binds to a CD4 extra U.S. PATENT DOCUMENTS cellular region with high a?inity and also exhibits a high 7,037,496 B2* 5/2006 Ghrayeb et al. ......... .. 424/1331 ADCC activity or a high CDC activity; a hybridoma which 7,214,775 B2 5/2007 Hanai et al. produces the antibody; a DNA which encodes the antibody; a 2006/0183195 A1 8/2006 Lonberg et al. vector which contains the DNA; a transforrnant obtainable by 2007/0148165 A1 6/2007 Shitara et al. introducing the vector; a process for producing an antibody or an antibody fragment thereof using the hybridoma or the FOREIGN PATENT DOCUMENTS transformant; and a therapeutic agent using the antibody or WO 9709351 A1 3/1997 the antibody fragment thereof or a diagnostic agent using the WO 97/13852 A1 4/1997 antibody or the antibody fragment thereof. WO 2007/011041 A1 1/2007 WO 2007009469 A2 1/2007 4 Claims, 15 Drawing Sheets US 8,877,913 B2 Page 2 (56) References Cited pincott Williams &Wilkins, Hagertown, MD, US, Feb. I, 2007, vol. 30, No. 2, pp. 190-202. European Patent Of?ce, Search Report dated Dec. 19, 2012 issued in OTHER PUBLICATIONS counterpart European Application No. 098350622. Choy, Ernest H. S., et al., “Chimaeric anti-CD4 monoclonal antibody Samuel Troadec et al., “Biological activities on T lymphocytes of a cross-linked by monocyte Fc gamma receptor mediates apoptosis of baculovirus-expressed chimeric recombinant IgGl antibody With human CD4 lymphocytes,” European Journal of Immunology, Oct. speci?city for the CDR3-like loop on the D1 domain of the CD4 1993, vol. 23, No. 10, pp. 2676-2681. molecule”, Clinical Immunology, 2006, 119: 38-50. Japanese Patent Of?ce, Communication dated Aug. 13, 2013 issued Troadec, Samuel, et al., “In Vitro Antitumoral Activity of in counterpart Japanese Patent Application No. 2010-544182. Baculovirus-expressed Chimeric Recombinant Ant-CD4 Antibody l3B8.2 on T-cell Lymphomas”, Journal of Immunotherapy, Lip * cited by examiner US. Patent NOV. 4, 2014 Sheet 3 0f 15 US 8,877,913 B2 E6 X.mwoizz. or or am£09 382ang 5.0 C) CJO C) O C LON 00 o 6.0 .Em@ N ' .EmQ ow om ow ow Ausualu| eoueoseuom :1 ueew Ausualu| GOUSOSGJOHH ueaw 695 omw0\\X$82z¢T wS66F2 >uo£E<5:250:00EEBE w 6.0S2F woi8852;? mX \\\i.J o mmOmImm oow wOE........................................................... wwowzxi. w3535$ .Eim .EmQ w:72: m8 M.08 w2: m3 wo w 0 W o m u US. Patent NOV. 4, 2014 Sheet 4 0f 15 US 8,877,913 B2 |I.l$032! 30%?III owI lIol£032! .0v1.56I owI .Ev 6.0ToPor00? __o >no£E<cozmbcmocoo3853 cowI owI owI (%) Ammxolol?o lemmas US. Patent NOV. 4, 2014 Sheet 5 0f 15 US 8,877,913 B2 t. IZNEQ58> PIO MOnL IIVAI mmm 5.6956<z%285%.<I>4>< Em;£20FE>28:#9£20 6:Q:22<zm FP 2:0me<206E5 <@220Q.. 429%58> man; L/Qfl. 960@556v6>von=c< mEochf US. Patent NOV. 4, 2014 Sheet 6 0f 15 US 8,877,913 B2 992;? ., 20 22a 4 , Q Eoom 053 Emozm,.S US. Patent NOV. 4, 2014 Sheet 7 0f 15 US 8,877,913 B2 :55:9meEmpwcoo “6:562:5war5mm:_ a?52 waxy-.535 a "_2.meo:oEmoExmBU? 1.5556353.63»; mocmsamm US. Patent NOV. 4, 2014 Sheet 8 0f 15 US 8,877,913 B2 memiai IQ!$8 +mm?TmOm '7mvoizx 9622!III IlmTlE532! mwoizx_ +mvow?x .Em >uo£E<cozmbcmocooSEES To Wm ON me m.o 0.0 m6 (WUSLVCIO) QQUBQJOSQV US. Patent NOV. 4, 2014 Sheet 12 0f 15 US 8,877,913 B2 iWm.:4:1......................................J 2" LL mm.8w/ 32Q282S2Q282 8212!lo!am, £82!l®l “30¢lila Tmow.-.<---ea.............a............ ........ o0m.o m.m2 mm.8 m.M 22.mma»2_ . m/w2( m.w. Dm >uonzc<cosmzcwocoo@505 mym.So 2822: 2.3Q 52 US. Patent NOV. 4, 2014 Sheet 13 0f 15 US 8,877,913 B2 2.omQwcm 2dm 923BEE.Lotscornuc?awc?h lvmlm>=mmmz6.530 2522!+ mmvm+ oocw aomm aoom comm caou cam? coo? cam US. Patent NOV. 4, 2014 Sheet 15 0f 15 US 8,877,913 B2 mmv2.owmmoncwmw 2.91 39:32v6w>m0BEE.coszm?wcm;6am |<|38%.328Sa- |X|2.3me35:00 lo]38522:325:. Ill#852com.323:. cocv ocom cccw ocov (sww) ewn|0/\ Joumi US 8,877,913 B2 1 2 ANTI-CD4 ANTIBODY Patent Literature 5), and the like. These antibodies are anti bodies which exert their medicinal ef?cacy by speci?cally CROSS-REFERENCE TO RELATED attacking CD4-expressing cells which are target cells, and it is APPLICATIONS considered that the mechanism of medicinal ef?cacy is mainly due to an ADCC activity (Non-Patent Literatures 6 This is a divisional of Us. patent application Ser. No. and 7). Meanwhile, these antibodies are shown to be devoid of 12/647,698 (allowed), ?led Dec. 28, 2009, which claims pri a CDC activity which is generally known as one of the main ority to Us. Provisional Patent Application No. 61/141,393, mechanism of medicinal ef?cacy of therapeutic antibodies, ?led Dec. 30, 2008, and Japanese Patent Application No. like ADCC (Non-Patent Literatures 6 and 7). 2008-331904 ?led Dec. 26, 2008, the contents of which are incorporated herein by reference in their entirety. The potency of CDC activity is different depending on the subclass of antibodies, and human IgG1 and IgG3 subclasses BACKGROUND OF THE INVENTION have a high CDC activity. It is known that the intensity of CDC activity among the subclasses is generally in the order of 1. Field of the Invention IgG3 ngG1>>IgG2ngG4. In addition, there is a case where The present invention relates to a monoclonal antibody or the CDC activity of an antibody is exerted or is not exerted an antibody fragment thereof, which binds to human CD4 depending on an antigen to which the antibody binds (Non extracellular region with a high af?nity and also exhibits a Patent Literature 11).
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