US 20100272636A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0272636A1 Byrd et al. (43) Pub. Date: Oct. 28, 2010 (54) ANTI-CD74 IMMUNOCONJUGATES AND filed on Mar. 1, 2002, provisional application No. METHODS OF USE 61/265,999, filed on Dec. 2, 2009. (75) Inventors: John C. Byrd, Columbus, OH Publication Classification (US); David M. Goldenberg, (51) Int. Cl. Hansen, Picayune, MS (US) A 6LX 9/27 (2006.01) A6II 5L/12 (2006.01) SISNOSE RNc. A61K 38/19 (2006.01) 3OO AMERICAN ROAD A638/2A638/20 :08:2006.O1 MORRIS PLAINS, NJ 07950 (US) A6IP35/00 (2006.01) (73) Assignees: THE OHO STATE 39t. E: 308: UNIVERSITY, Columbus, OH A6IP37/06 (2006.015 (US); IMMUNOMEDICS, INC., Morris Plains, NJ (US) (52) U.S. Cl. ..................... 424/1.21; 424/450; 424/178.1; 424/179.1; 424/183.1; 424/85.1; 424/85.2: (21) Appl. No.: 12/789,575 424/85.4; 424/85.5; 424/85.6; 424/85.7 (22) Filed: May 28, 2010 (57) ABSTRACT O O Disclosed are compositions that include anti-CD74 immuno Related U.S. Application Data conjugates and optionally a therapeutic and/or diagnostic (63) Continuation-in-part of application No. 10/706,852, agent. In preferred embodiments, the immunoconjugates filed on Nov. 12, 2003, which is a continuation-in-part comprise one or more anti-CD74 antibodies or antigen-bind of application No. 10,314 330, filed on Dec. 9, 2002 ing fragments thereof, conjugated to a liposome or micelle. which is a continuation of application No. 09/965,796, Also disclosed a methods for preparing the immunoconju filed on Oct. 1, 2001, which is a continuation of appli- gates and using the immunoconjugates in diagnostic and cation No. 09/307,816, filed on May 10, 1999, now therapeutic procedures. In certain preferred embodiments, Pat. No. 6 306 393. said application No. 10,706 852 is the therapeutic methods comprise administering to a subject a continuation-in-part of application No. 10/350,096, with a CD74-expressing disease al anti-CD74 immunocon filed on Jan. 24, 2003, which is a continuation of appli- jugate and thereby inducing apoptosis of CD74-expressing cation No. 09/590,284 filed on Jun. 9, 2000, now Pat. cells. In more preferred embodiments, the CD74 immuno No. 7074,403 said application No. 10,706 852 is a conjugate is capable of inducing cell death in the absence of continuation-in-part of application No. 10/377,122, any other therapeutic agent, although Such agents may be filed on Mar. 3, 2003, now Pat. No. 7,312.318 optionally administered prior to, together with or Subsequent • - s s • L vs - s- a 1- s- u Y- - to administration of the anti-CD74 immunoconjugate. The (60) Provisional application No. 60/478,830, filed on Jun. compositions may be part of a kit for administering the anti 17, 2003, provisional application No. 60/360,259, CD74 immunoconjugates or compositions. Patent Application Publication Oct. 28, 2010 Sheet 1 of 11 US 2010/0272636 A1 06 O8VÌ280$30£.09 +--~~~~----–—~~+–+~---+-+~~--~~~~-->•+~~~~+-~~+– 0£02O? +–~~~~~~~+–+~-+-~~+–+----+––-+ +~––+~~~~-~---+~-+-+–+--+- +–~~+~~~~~~+–+~--–+----–-+--------- O[IX{T06{{\f00 VI"OIH V?Zg0GO? ZHGIOTYICIO £&ICIO Patent Application Publication Oct. 28, 2010 Sheet 2 of 11 US 2010/0272636 A1 D8VÌLZOZ0I 0$3[+–~~+–+--------–+~~~~---+~~+–+-------~--~~~~+ OLZ+~+–~~~+--~---{---–+~~~~~~+--~---------+- 06+––+--------–+~~~~~~~+----~~~~ L0980O £€––+~~+~---------–+----+----—- £0£TH0G0CI I06O I?a"IyI,9,0?T?T?T?T?TSSTS-53); Z?OTOTRICHO €YICIO Patent Application Publication Oct. 28, 2010 Sheet 3 of 11 US 2010/0272636 A1 6G O8T 68 ÇIT -~+--+-~~~~~~-----+––+–-+----+----------+ ––+~+------~+–+------–+ “?IHVZ ~~–+–~-~~+-~~+~~+-–+-+–+---+- IQSGI HA?TT3 ZHOTOTA?CIO Patent Application Publication Oct. 28, 2010 Sheet 4 of 11 US 2010/0272636 A1 06 G G8 ITog/III6? O8T+––+-+–+–~~+–+---- 0L2+~~------+-–+--~-----+-----––+~+~-+-----+~+ I*XIIT».I,9&T?T?TAT?TSTST?TS3);30 £&ICIO 9+–+69 MALT"|0 ZHOTOIYICIO Patent Application Publication Oct. 28, 2010 Sheet 7 of 11 US 2010/0272636 A1 6G 69 O8T O9£ ©I V†“?IH +--------––+~~---+--+--+~---++––+~+–+------------------ +–~---+~~----+~+–+–~+----~~~~~ +–~~+~~+------–+-------------–+~+~~--------–—+ +–~---+~~--~+~~~~+–+~--+–~+~ £ICIO HA?TTUI ZAICIOTxICIO Patent Application Publication Oct. 28, 2010 Sheet 8 of 11 US 2010/0272636A1 06 I09 GG LZO T80 A"IS –~--------+----~~+----------------+–+~–+-~~++––+ –—–+--------~~+–··-----+----+-–+~~+-~-+––+- –+---+----------~––+--+–+–+------------+------+-+–-~~- –+-+----------+---------+----------+------------- XHALTITUI —º—THOTO Patent Application Publication Oct. 28, 2010 Sheet 9 of 11 US 2010/0272636 A1 8IS“?IJI (snou va) amisodid% |- VS"OIH |Ir|Ir] 8ASO Patent Application Publication Oct. 28, 2010 Sheet 10 of 11 US 2010/0272636 A1 easo One S-pers Aften OAO + Wee. ano + 34-gue oneSen? A?esin eur OAD + V ele w ele-- OAO + 3-rule + eIN oute + ew OAO + 3-le le: Patent Application Publication Oct. 28, 2010 Sheet 11 of 11 US 2010/0272636 A1 TH-961euosodinpeyeenum 09"?IJI W 000 US 2010/0272636 A1 Oct. 28, 2010 ANT-CD74. IMMUNOCONUGATES AND bind to a known tumor associated antigen (TAA) or to an METHODS OF USE antigen associated with infectious diseases or other disease States. CROSS-REFERENCE TO RELATED 0006. One such tumor-associated antigen is CD74, which APPLICATIONS is an epitope of the major histocompatibility complex (MHC) 0001. This application is a continuation-in-part of appli class II antigen invariant chain, Ili, present on the cell Surface cation Ser. No. 10/706,852, filed Nov. 12, 2003, which and taken up in large amounts of up to 8x10" molecules per claimed the benefit under 35 U.S.C. 119(e) of provisional cell per day (Hansen et al., 1996, Biochem. J., 320: 293-300). application Ser. No. 60/478,830, filed on Jun. 17, 2003, and CD74 is present on the cell surface of B-lymphocytes, mono which was a continuation-in-part of application Ser. No. cytes and histocytes, human B-lymphoma cell lines, melano 10/314,330, filed on Dec. 9, 2002, which was a continuation mas, T-cell lymphomas and a variety of other tumor cell of application Ser. No. 09/965,796, filed on Oct. 1, 2001, types. (Hansen et al., 1996, Biochem.J.,320:293-300) CD74 which was a continuation of application Ser. No. 09/307,816, associates with C/B chain MHC II heterodimers to form MHC filed on May 10, 1999, now U.S. Pat. No. 6,306.393. U.S. Ser. II CBIi complexes that are involved in antigen processing and No. 10/706,852 was also a continuation-in-part of application presentation to T cells (Dixon et al., 2006, Biochemistry Ser. No. 10/350,096, filed on Jan. 24, 2003, which was a 45:5228-34; Loss et al., 1993, J Immunol 150:3187-97: continuation of application Ser. No. 09/590,284, filed on Jun. Cresswell et al., 1996: Cell 84:505-7). 9, 2000, now U.S. Pat. No. 7,074,403. U.S. Ser. No. 10/706, 0007 CD74 also plays an important role in cell prolifera 852 was also a continuation-in-part of application Ser. No. tion and Survival. Binding of the CD74 ligand, macrophage 10/377,122, filed on Mar. 3, 2003, now U.S. Pat. No. 7,312, migration inhibitory factor (MIF), to CD74 activates the 318, which claimed the benefit of provisional application Ser. MAP kinase cascade and promotes cell proliferation (Lenget No. 60/360,259, filed on Mar. 1, 2002. al., 2003, J Exp Med 197:1467–76). Binding of MIF to CD74 0002. This application claims the benefit under 35 U.S.C. also enhances cell survival through activation of NF-kB and 119(e) to provisional application Ser. No. 61/265,999, filed Bcl-2 (Lantner et al., 2007, Blood 110:4303-11). Dec. 2, 2009. All of the above-identified applications and 0008 Murine LL1 (mLL1 or murine anti-CD74 antibody) patents are incorporated herein by reference in their entire is a specific monoclonal antibody (mAb) reactive with CD74. ties. Cell surface-bound LL1 is rapidly internalized to the lysoso mal compartment and quickly catabolized, much faster than FEDERALLY FUNDED RESEARCH other antibodies, such as anti-CD19 or anti-CD22 (Hansen et 0003. This work was supported in part by National Cancer al., 1996, Biochem. J., 320: 293-300). LL1 was reported to Institute grants CA95426, CA103985 and CA81534-02. The exhibit the highest rate of accumulation inside B cells of any Federal Government may have certain rights in the invention. of the antibodies tested (Griffiths et al., 2003, Clin Cancer Res 9:6567-71). FIELD OF THE INVENTION 0009 Murine LL1 was developed by fusion of mouse myeloma cells with splenocytes from BALB/c mice immu 0004. The present invention concerns compositions and nized with preparations from the Raji B-lymphoma cell line methods of use of liposomes attached to targeting molecules, (called EPB-1 in Pawlak-Byczkowska et al., Can. Res., 49: Such as antibodies, antibody fragments or antibody fusion 4568 (1989)). The clinical use of mLL1, just as with most proteins. More particularly, the antibodies, fragments or other promising murine antibodies, has been limited by the fusion proteins may bind to a tumor associated antigen, infec development in humans of a human anti-mouse antibody tious disease associated antigen or other disease associated (HAMA) response. A HAMA response is generally not antigen. Even more particularly, the targeting molecule may observed following injection of mLL1 Fab', as evidenced in a bind to the invariant chain (Ii) of the HLA-DR complex, also bone marrow imaging study using an mLL1 Fab" labeled with known as CD74. An exemplary anti-CD74 antibody is mil "Tc. Juweidet al., Nuc. Med. Comm. 18: 142-148 (1997). atuZumab (hLL1). The antibody conjugated liposome is of However, in some therapeutic and diagnostic uses, a full use for the treatment of a variety of diseases, such as autoim length anti-CD74 antibody may be preferred. This use of the mune disease, immune dysregulation disease, cancer, lym full-length anti-CD74 antibody can limit the diagnostic and phoma, leukemia, chronic lymphocytic leukemia, follicular therapeutic usefulness of Such antibodies and antibody con lymphoma, diffused large B cell lymphoma, multiple jugates, not only because of the potential anaphylactic prob myeloma or non-Hodgkin’s lymphoma.