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(12) United States Patent (10) Patent No.: US 6,277.375 B1 Ward (45) Date of Patent: Aug

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(12) United States Patent (10) Patent No.: US 6,277.375 B1 Ward (45) Date of Patent: Aug USOO6277375B1 (12) United States Patent (10) Patent No.: US 6,277.375 B1 Ward (45) Date of Patent: Aug. 21, 2001 (54) IMMUNOGLOBULIN-LIKE DOMAINS WITH Horton, Hunt, Ho, Pullen, Pease, “Engineering hybrid genes INCREASED HALF-ILIVES without the use of restriction enzymes: gene Splicing by overlap extension”, Gene , 77:61-68, 1989. (75) Inventor: Elizabeth Sally Ward, Dallas, TX (US) Israel, Patel, Taylor, Marshak-Rothstein, Simister, "Requirement for a B2-microglobulin associated Fc recep (73) Assignee: Board of Regents, The University of tor for acquisition of maternal IgG by fetal and neonatal Texas System, Austin, TX (US) mice’, J. Immunol., 154:6246–6251, 1995. (*) Notice: Subject to any disclaimer, the term of this Israel, Wilsker, Hayes, Schoenfeld, Simister, “Increased patent is extended or adjusted under 35 clearance of IgG in mice that lack B2-microglobulin: pos U.S.C. 154(b) by 0 days. sible protective role for FcRn”, Immunol., 89:573–578, 1996. (21) Appl. No.: 08/811,463 Junghans, AnderSon, “The protection receptor for IgG catabolism is the B2-microglobulin-containing neonatal (22) Filed: Mar. 3, 1997 intestinal transport receptor, Proc. Natl. Acad. Sci. USA, 93:5512-5516, 1996. (51) Int. Cl." ......................... A61K.39/395; CO7K 16/00 (52) U.S. Cl. ...................................... 424/133.1; 530/387.3 Kabat, Wu, Perry, Gottesman, Foeller, “Sequences of pro (58) Field of Search ....................... 530/387.3; 424/133.1 teins of immunological interest', U.S. Department of Health and Human Services, 1991. (56) References Cited Kim et al., “Catabolism of the Murine IgG1 Molecule: FOREIGN PATENT DOCUMENTS Evidence that Both CH2-CH3 Domain Interfaces are Required for Persistence of IgG1 in the Circulation of O327 378 8/1989 (EP). Mice,” Scand. J. Immunol., 40:457-465, 1994. WO 93/22332 11/1993 (WO). WO 94/04689 Kim et al., “Evidence That the Hinge Region Plays a Role 3/1994 (WO). in Maintaining Serum Levels of the Murine IgG1 Mol OTHER PUBLICATIONS ecule,” Mol. Immunol., 32(7):467-475, 1995. Batra, et al., “Insertion of Constant Region Domains of Kim, Tsen, Ghetie, Ward, “Identifying amino acid residues Human IgG into CD4-PE40 Increases its Plasma that influence plasma clearance of mouse IgG1 fragments by Half-Life.” Molecular Immunology, 30(4):379-386, 1993. site directed mutagenesis”, Eur: J. Immunol., 24:542-548, Wawrzynczak, et al., “Blood Clearance in the Rat of a 1994. Recombinant Mouse Monoclonal Antibody Lacking the Kim, Tsen, Ghetie, Ward, “Localization of the site of the N-Linked Oligosaccharide Side Chains of the C2 murine IgG1 molecule that is involved in binding to the Domains,” Molecular Immunology, 29(2):213-220, 1992. murine intestinal Fc receptor, Eur: J. Immunol., International Search Report dated Aug. 7, 1997 PCT/US97/ 24:2429–2434, 1994. O3321. Ames, Prody, Kustu, "Simple, rapid and quantitative release Kristoffersen, Matre, “Co-localisation of the neonatal FcB of periplasmic proteins by chloroform,” J. Bacteriol., receptor and IgG in human placental term syncytiotropho 160:1181-1183, 1984. blast”, Eur: J. Immunol., 26:1668–1671, 1996. Brambell, Hemmings, Morris, “A theoretical model of gam maglobulin catabolism", Nature, 203:1352–1355, 1964. (List continued on next page.) Burmeister, Huber, Bjorkman, “Crystal structure of the complex of rat neonatal Fc receptor with Fc', Nature, Primary Examiner David Saunders 372:379-383, 1994. (74) Attorney, Agent, or Firm-Fulbright & Jaworski Deisenhofer, “Crystallographic refinement and atomic mod (57) ABSTRACT els of human Fc Fragment and its complex from fragment B of protein A from Staphylococcus aureus at 2.9 and 2.8 à Disclosed are re combinant vectors encoding resolution”, Biochemistry, 20:2361-2370, 1981. immunoglobulin-like domains and portions thereof, Such as Duncan, Winter, “The binding site for C1q on IgG”, Nature, antibody Fc-hinge fragments, Subfragments and mutant 332:738–740, 1988. domains with extended biological half lives. Methods of Duncan, Woof, Partridge, Burton, Winter, “Localization of producing large quantities of Such domains, heterodimers, the binding site for the human high affinity Fc receptor on and fusion proteins following expression by host cells are IgG”, Nature, 332:563-564, 1988. also reported. Described are antibody Fc and Fc-hinge Edelman, Cunningham, Gall, Gottlieb, Rutishauser, Waxdal, domains, which have the same in Vivo Stability as intact “The covalent structure of an entire YG molecule', Proc. antibodies, and domains engineered to have increased in Natl. Acad. Sci., USA, 63:78–85, 1969. vivo half lives. These DNA constructs and protein domains Ghetie, Hubbard, Kim, Tsen, Lee, Ward, “Abnormally short will be useful as templates for in Vitro mutagenesis and high serum half-lives of IgG in 32-microglobulin deficient resolution Structural Studies; for immunization and vaccina mice”, Eur: J. Immunol., 26:690–696, 1996. tion; and for the production of recombinant antibodies or Hoogenboom, Griffiths, Johnson, Chiswell, Hudson, Winter, chimeric proteins with increased Stability and longevity for “MultiSubunit proteins on the Surface of filamentous phage: therapeutic and diagnostic uses. methodologies for displaying antibody (Fab) heavy and light chains”, Nucl. Acids Res., 19:4133–4137, 1991. 4 Claims, 15 Drawing Sheets US 6,277.375 B1 Page 2 OTHER PUBLICATIONS Sarmay, Lund, ROZSnyay, Gergely, Jefferis, "Mapping and comparison of the interaction sites on the Fc region of IgG Leach, Sedmark, Osborne, Rahill, Lairmore, Anderson, responsible for triggering antibody dependent cellular cyto "Isolation from human placenta of the IgG transporter, toxicity (ADC) through different types of human Fc recep FcRn, and localization to the syncytiotrophoblast”, J. Immu tor', Mol. Immunol., 29:633–639, 1992. nol., 157:3317–3322, 1996. Marks, Hoogenboom, Bonnett, McCafferty, Griffiths, Win Simister, Story, Chen, Hunt, “An IgG-transporting Fc recep ter, “By-passing immunisation: human antibodies from tor expressed in the Syncytiotrophoblast of human placenta', V-gene libraries displayed on phage', J. Mol. Biol., Eur: J. Immunol, 26:1527-1531, 1996. 222:581-597, 1991. Medesan, MateSoi, Radu, Ghetie, Ward, “Delineation of the Story, Mikulska, Simister, “A major histocompatibility com amino acid residues involved in transcytosis and catabolism pleX class I-like Fc receptor cloned from human placenta: of mouse IgG1’, J. Immunol., in press, 1997. possible role in transfer of immunoglobulin G from mother Medesan, Radu, Kim, Ghetie, Ward, “Localization of the to fetus”, J. Exp. Med., 180:2377–2381, 1994. Site of the IgG molecule that regulates maternofetal trans Wallace, Rees, “Studies on the Immunoglobulin-GFc frag mission in mice”, Eur: J. Immunol., 26:2533-2536, 1996. ment receptor from neonatal rat Small intestine', Biochem. Popov, Hubbard, Kim, Ober, Ghetie, Ward, “The Stoichi J., 188:9-16, 1980. ometry and affinity of interaction of murine Fc fragments with the MHC class I-related receptor, FcRn”, Mol. Immu Ward, “Secretion of soluble T cell receptor fragments from nol, 33:521-530, 1996. recombinant Escherichia coli cells,” J. Mol. Biol., Raghavan, Bonagura, Morrison, Bjorkman, “Analysis of the 224:885–890, 1992. pH dependence of the neonatal receptor/immunoglobulin G Ward, “VH shuffling can be used to convert an Fv fragment interaction using antibody and receptor variants”, Biochem of anti-hen egg lysozyme Specificity to one that recognizes istry, 34:14649–14657, 1995. Roberts, Guenthert, Rodewald, “Isolation and characterisa a T cell receptor Vol.” Mol. Immunol., 32:147–156, 1994. tion of the Fc receptor from the fetal yolk sac of the rat', J. Ward, Guessow, Griffiths, Jones, Winter, “Binding activities Cell. Biol., 111:1867-1876, 1990. of a repertoire of Single immunoglobulin variable domains Rodewald, Kraehenbuhl, “Receptor-mediated transport of Secreted from Escherichia coli,” Nature, 341:544-546, IgG”, J. Cell. Biol., 99:154s-164s, 1984. 1989. U.S. Patent Aug. 21, 2001 Sheet 1 of 15 US 6,277.375 B1 U.S. Patent Aug. 21, 2001 Sheet 2 of 15 US 6,277.375 B1 s CN s CD L O N. Od CO CN 2 T t 2 CD S. c. Ch \, O C) cy O CN O C/if O - - - O O O O O O O O C O Co y O O r C O - % OF CONTROL (% RADIO LABEL REMAINING) U.S. Patent Aug. 21, 2001 Sheet 3 of 15 US 6,277.375 B1 CN Sc CD LL g s O CO O O g C/O re- es CDS O l O st O2 ge A Cy S SC O CN O SC SC ^ SE <<!. O S O 2 - % OF CONTROL (% RADIO LABEL REMAINING) U.S. Patent US 6,277.375 B1 CO CO r CN O ng/107 Cells U.S. Patent Aug. 21, 2001 Sheet 5 of 15 US 6,277.375 B1 Percentage of Initial Radioactivity U.S. Patent Aug. 21, 2001 Sheet 6 of 15 US 6,277,375 B1 5SO s sc C LL Hs 2 g (? < O S. go 5 CDto CO r er CN 2N2 C -69C O O O r se y PERCENT OF RADIOACTIVITY U.S. Patent Aug. 21, 2001 Sheet 7 of 15 N&SpsgsS US 6,277.375 B1 o O O. O. O. O. C. O. O. L. O. C s Old Co. oO o N. N. RESPONSE (RU) U.S. Patent Aug. 21, 2001 Sheet 8 of 15 US 6,277.375 B1 O O O O C O O S. S S CN CN s RESPONSE (RU) U.S. Patent Aug. 21, 2001 Sheet 9 of 15 US 6,277.375 B1 100 O FC-hybrid CH2-hinge dimer HQ-31 O/HN-433 0.1 CH2-hinge On One S CH3 FV 0.01 O 20 40 60 80 100 FIG. 7 U.S. Patent Aug. 21, 2001 Sheet 10 of 15 US 6,277.375 B1 Percentage of transmissions ( ) U.S. Patent Aug. 21, 2001 Sheet 11 of 15 US 6,277.375 B1 O O C Cld L .
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