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Wo 2007/073499 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 28 June 2007 (28.06.2007) WO 2007/073499 A2 (51) International Patent Classification: Not classified BRUCKHEIMER, Elizabeth [US/US]; 4312 Frankfort (21) International Application Number: Drive, Rockville, MD 20853 (US). SCHLERETH, PCT/US2006/048995 Bernd [DE/DE]; Keltenstr. 13, 821 10 Germering (DE). HAMMOND, Scott, A. [US/US]; 3216 Llewellyn Field (22) International Filing Date: Road, Olney, MD 20832 (US). LUTTERBUESE, RaIf 2 1 December 2006 (21.12.2006) [DE/DE]; Fliederstr. 11, 82061 Neuried (DE). KIENER, (25) Filing Language: English Peter, A. [US/US]; 1017 Gorky Drive, Potomac, MD (26) Publication Language: English 20854 (US). BAEURELE, Patrick [DE/DE]; Waldprom- enade 18c, 82131 Gauting (DE). LUTTERBUESE, Petra (30) Priority Data: [DE/DE]; Fliederstr. 11, 82061 Neuried (DE). 60/753,368 2 1 December 2005 (21.12.2005) US (71) Applicants (for all designated States except US): MED- (74) Agents: INSOGNA, Anthony M. et al; Jones Day, 222 IMMUNE, INC. [US/US]; One Medimmune Way, East 41st Street, New York, NY 10017-6702 (US). Gaithersburg, MD 20878 (US). MICROMET AG (81) Designated States (unless otherwise indicated, for every [DE/DE]; Staffelseestr. 2, 81477 Munich (DE). kind of national protection available): AE, AG, AL, AM, (72) Inventors; and AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, (75) Inventors/Applicants (for US only): KINCH, Michael, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FT, S. [US/US]; 19627 Hoover Farm Drive, Laytonsville, MD GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, 20883 (US). ROFF, Shannon [US/US]; 1630 Brimfield JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, Circle, Eldersburg, MD 21784 (US). KUFER, Peter LT, LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MY, [DE/DE]; Am Kapellenacker 13, 85368 Moosburg (DE). MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, [Continued on next page] (54) Title: EPHA2 BITE MOLECULES AND USES THEREOF (57) Abstract: The present invention relates to bispecific KA2 Variable Light Chain single chain antibodies comprising a first binding domain that irnmunospecifEcally binds to the T-cell antigen CD3 and a second binding domain that immunospecifically binds to the EphA2 receptor. Such bispecific single chain antibodies are encompassed by the term "EphA2-BiTEs." The present invention further relates to methods and compositions designed for the treatment, prevention and/or management of disorders associated with aberrant expres sion and/or activity of EphA2. Such disorders include, but are not limited to, cancer, non-cancer hyperproliferative cell disorders, and infections. The invention further relates to vectors comprising polynucleotides encoding the EphA2 -BiTEs of the invention, host cells transformed therewith, and their use in the production of said EphA2-BiTEs. The invention also provides compositions, including EA2 Variable Heavy Chain pharmaceutical compositions, comprising any of the aforementioned EphA2-BiTEs, polynucleotides or vectors either alone or in combination with one or more prophylactic or therapeutic agents. Also disclosed are methods of screening for said EphA2 -BiTEs and kits comprising any of the aforementioned compositions and diagnostic reagents. RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, Published: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. — without international search report and to be republished upon receipt of that report (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, ~ GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), eSCnp W H European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, NL, PL, PT, For two-letter codes and other abbreviations, refer to the "Guid- RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, ance Notes on Codes and Abbreviations "appearing at the begin- GN, GQ, GW, ML, MR, NE, SN, TD, TG). ning of each regular issue of the PCT Gazette. EPHA2 BiTE MOLECULES AND USES THEREOF This application claims benefit of U.S. Provisional Application No. 60/753,368, filed December 21, 2005, which is incorporated by reference herein in its entirety. 1. FIELD OF THE INVENTION [0001] The present invention relates to bispecific single chain antibodies comprising a first binding domain that immunospecifically binds to the T-cell antigen CD3 and a second binding domain that immunospecifically binds to the EphA2 receptor. Such bispecific single chain antibodies are encompassed by the term "EphA2-BiTEs." The present invention further relates to methods and compositions designed for the treatment, prevention and/or management of disorders associated with aberrant expression and/or activity of EphA2. Such disorders include, but are not limited to, cancer, non-cancer hyperproliferative cell disorders, and infections. The invention further relates to vectors comprising polynucleotides encoding the EphA2-BiTEs of the invention, host cells transformed therewith, and their use in the production of said EphA2-BiTEs. The invention also provides compositions, including pharmaceutical compositions, comprising any of the aforementioned EphA2-BiTEs, polynucleotides or vectors either alone or in combination with one or more prophylactic or therapeutic agents. Also disclosed are methods of screening for said EphA2-BiTEs and kits comprising any of the aforementioned compositions and diagnostic reagents. 2. BACKGROUND OF THE INVENTION 2.1 EphA2 [0002] EphA2 is a 130 kDa receptor tyrosine kinase that is expressed in adult epithelia, where it is found at low levels and is enriched within sites of cell-cell adhesion (Zantek et al., 1999, Cell Growth & Differentiation 10(9):629-38; Lindberg et al., MoI. & Cell. Biol. 10:6316, 1990). This subcellular localization is thought to play a role in contact inhibition through the interaction of EphA2 with its ligands (known as EphrinsAl to A5) that are anchored to the cell membrane on adjacent cells (Eph Nomenclature Committee, 1997, Cell 90:403-04; Cheng et al., 2002, Cytokine & Growth Factor Rev. 13:75-85). Engagement of EρhA2 with its ligand results in autophosphorylation of EphA2 and its subsequent degradation (Walker-Daniels et al., 2002, MoI. Cancer. Res. l(l):79-87; Carles- Kinch et al., 2002, Cancer Res. 62(10):2840-47). This signaling cascade also initiates downstream events that negatively regulate attachment to extracellular matrix adhesion molecules and thereby regulate cell growth and migration (Zantek et al., 1999, Cell Growth & Differentiation 10(9):629-38; Miao et al., 2000, Nat. Cell Biol. 2(2):62-69; Zelinski et al., 2001, Cancer Res. 61(5):2301-06). [0003] EphA2 has been shown to be overexpressed in a number of different tumor types including melanoma, renal cell carcinoma, breast, prostate, colon, esophageal, cervical, lung, ovarian and bladder cancers (Carles-Kinch et al., 2002, Cancer Res. 62(10):2840-47). The highest levels of EphA2 expression are observed in the most aggressive cells, suggesting a role for EphA2 in disease progression. High levels of EphA2 have also been correlated with poor survival for non-small cell lung, esophageal, cervical and ovarian cancers (Kinch et al., 2003, Clin. Cancer Res. 9(2):613-18; Miyazaki et al., 2003, Int. J. Cancer 103(5) 657-63; Wu et al., 2004, Gynecol. Oncol. 94(2):3 12-19; Thaker et al., 2004, Clin. Cancer Res. 10(1 5):5 145-50). Additionally, in pre-clinical models, it has been demonstrated that exogenous expression of EphA2 is sufficient to render a non- tumorigenic cell line tumorigenic in vitro and in vivo (Zelinski et al., 2001, Cancer Res. 61(5):2301-06). 2.2 BiTE ® Molecules [0004] Bispecific T-cell engagers, or BiTEs , are a form of bispecifϊ c antibodies that are based on tandemly arranged single-chain antibodies (reviewed in Wolf et al., 2005, Drug Discovery Today: in press). They form a single polypeptide chain of approximately 55 kDa and are secreted by Chinese hamster ovary (CHO) cells as a mixture of monomers and dimers. With one arm, BiTEs ® bind to the epsilon (ε) subunit of human CD3, a protein component of the signal-transducing complex of the T-cell receptor on T-cells. With the other arm, BiTEs® recognize an antigen on target cells. T-cell activation is only seen when BiTEs® are presented to T-cells on the surface of target cells. [0005] BiTEs® transiently tether T-cells and target cells. T-cell activation by BiTEs® involves upregulation of CD69, CD25 and various cell adhesion molecules, de novo expression and release of cytokines (e.g., IFN-γ, TNF-α, IL-6, IL-2, IL-4 and IL-10), upregulation of granzyme and perforin expression, and cell proliferation. Redirected target cell lysis by BiTEs® is independent of T-cell receptor specificity, presence of MHC class I and β2 microglobulin, and of any co-stimulatory stimuli. This independence from regular T-cell signals and recognition molecules may be explained by the induction through BiTEs® of regular cytolytic synapses and maximum membrane proximity. Displacement of negative regulatory proteins such as CD45 from BiTE®-induced synapses may alleviate the need for co-stimulation. [0006J BiTEs® show redirected lysis in vitro with previously unstimulated peripheral polyclonal CD8- and CD4-positive T-cells. No activity is seen with naϊ ve CD8- or CD4-positive T-cells. CD4 T-cells can upregulate granzyme B and perforin expression when stimulated with BiTEs® and thereby contribute to CD8-mediated target cell lysis. In vitro, redirected lysis is seen at low picomolar concentrations, suggesting that very low numbers of BiTE molecules need to be bound to target cells for triggering T-cells.
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