Therapeutic use of anti-CS1 antibodies

78 Pages·2013·6.3 MB·English

US008436146B2
(12) Uni.t ed States Patent (10) Patent No.: US 8,436,146 B2
Williams et al. (45) Date of Patent: *May 7, 2013
(54) THERAPEUTIC USE OF ANTI-CS1 WO WO00/47602 A1 8/2000
ANTIBODIES WO WO00/73454 A1 12/2000
WO WO01/16318 A2 3/2001
. . WO WO01/46260 A2 6/2001
(75) Inventors: Marna Williams, Palo Alto, CA (US); J. W0 Wool/68848 AZ 90001
Ylln T80, MenlO Park, CA (Us); WO WO01/91793 A1 12/2001
Nicholas F. Landol?, Menlo Park, CA WO WO02/ 102993 A2 12/2002
((UUSS));; DGaavoi dLl Bu., PMoowuenrtsa,1 nFVai1refWax,, CCAA W0 Wow/029423 AZ 40003
(Us) wo WO2004/029207 A2 4/2004
(73) Assignee: AbbVie Biotherapeutics Inc., Redwood OTHER PUBLICATIONS
clty’ CA (Us) Angel de la Fuente, et al., “Molecular characterization and expres
* _ _ _ _ _ sion of a novel human leukocyte cell-surface marker homologous to
( ) Notice: Subject' to any disclaimer, the term ofth1s mouse Ly_9,,, Blood, V01‘ 97, NO‘ 11, pp‘ 35133520 (2001)‘
Pawnt 15 extended or adlusted under 35 Boles, et al., “2B4 (CD244) and CS1: novel members of the CD2
U.S.C. 154(b) by 0 days. subset of the immunoglobulin superfamily molecules expressed on
_ _ _ _ _ natural killer cells and other leukocytes,” Immunological Reviews,
This patent is subject to a terminal d1S- vol. 181, PP 234-249 (2001)
claimer. Boles, eta1., “Molecular cloning ofCSl, a novel human natural killer
cell receptor belonging to the CD2 subset of the immunoglobulin
( 21 ) A PP 1_ NO; 13/175 , 759 super fa m1' 1 y,”Immunogenetics, vo 1 . 52, pp. 302-307 2001 .
Bouchon, et al., “Cutting edge: activation of NK cell-mediated
- . cytotoxicity by a SAP-independent receptor of the CD2 family,”
(22) Flled' Jul‘ 1’ 2011 Journal ofImmunology, vol. 167, pp. 5517-5521 (2001).
_ _ _ Casset, et al., “A peptide mimetic of an anti-CD4 monoclonal anti
(65) Pm" Publlcatlon Data body by rational design,’’, BBRC, vol. 307, 198-205 (2003).
' ’ 2008 With Figure 1.
_ _ Genbank accession AB027233 (May 1999).
Related U-S- APPIICatIOII Data Genbank accession AF291815 (Aug. 2000).
(63) Continuation of application No. 12/397,026, ?led on Genbank accesslon ‘313390894 (Jun' 2001)‘
Genbank accession AF467909 (Jan. 2002).
Mar. 3, 2009, noW Pat. No. 8,088,898, Which is a
Genbank accession AJ271869 (Mar. 2000).
continuation of application No. 10/982,357, ?led on
Genbank accession H73135 (Oct. 1995).
Nov. 5, 2004, noW Pat. No. 7,709,610, Which is a Genbank accession H74227 (Oct. 1995).
continuation-in-part of application No. 10/842,011, Genbank accession NMi021181 (Mar. 2005).
?led on May 7, 2004, noW abandoned. Hillier, et al., “Generation and analysis of 280,000 human expressed
sequence tags,” Genome Research, vol. 6, pp. 807-828 (1996).
(60) Provisional application No. 60/469,211, ?led on May
Holm, et al., “Functional mapping and single chain construction of
8, 2003, provisional application No. 60/557,620, ?led
the anti-cytokeratin 8 monoclonal antibody TSl,” Molecular Biol
on Mar. 29, 2004, provisional application No. ogy, vol. 44, pp. 1075-1084 (2007).
60/557,622, ?led on Mar. 29, 2004, provisional Janeway et al., Immunobiology, 3rd. Edition Garland Press, pp. 3:7
application No. 60/557,621, ?led on Mar. 29, 2004. 3:11 (1997).
Janeway, et al., Immunobiology, 6th Edition, Garland Science, pp.
(51) Int. Cl. 110-112 (2004).
A61K 39/395 (2006.01) Kipriyanov, et al., “Generation of Recombinant Antibodies,”
Molecular Biotechnology (Review), vol. 12, pp. 173-201 (1999).
(52) U.S. Cl.
Kumaresan, et al., “CS1, a novel member of the CD2 family, is
USPC ................. .. 530/3871; 424/138.1; 424/133.1 homophilic and regulates NK cell function,” Molecular Immunology,
(58) Field of Classi?cation Search ...................... .. None vol. 39, pp. 1-8 (2002).
See application ?le for complete search history.
(Continued)
(56) References Cited
Primary Examiner * Yunsoo Kim
U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm * Dechert LLP
6,478,825 B1 11/2002 Winterbottom et al.
(57) ABSTRACT
6,607,898 B1 8/2003 Kopreski et a1.
7,041,499 B2 5/2006 Mathew et al. The present invention is directed to antagonists of CS1 that
7,169,565 B2 1/2007 Ruben
bind to and neutralize at least one biological activity of CS1.
8,008,450 B2 8/2011 Williams et al.
2002/0123617 A1 9/2002 Starling et al. The invention also includes a pharmaceutical composition
2003/0027986 A1 2/2003 Eaton et al. comprising such antibodies or antigen-binding fragments
2003/0099974 A1 5/2003 Lillie et al. thereof. The present invention also provides for a method of
preventing or treating disease states, including autoimmune
FOREIGN PATENT DOCUMENTS
disorders and cancer, in a subject in need thereof, comprising
EP 1033401 A2 9/2000
administering into said subject an effective amount of such
WO WO96/39518 A1 12/1996
antagonists.
WO WO98/42738 A1 10/1998
WO WO99/63088 A2 12/1999
WO WO00/11150 A1 3/2000 18 Claims, 5 Drawing Sheets
US 8,436,146 B2
Page 2
OTHER PUBLICATIONS RuiZ-Arguelles, et al., “Cell surface markers in multiple myeloma,”
Leo, et al., “Multiparameter analysis of normal and malignant human Mayo Clinic Proc., vol. 69, pp. 684-690 (1994).
Shields, et al., “High resolution mapping of the binding site on human
plasma cells: CD38++, CD56+, CD54+, clg+ is the common pheno
IgG1 for FcyRI, FcyRII, FcyRIII and FcRn and design of IgG1
type ofmyeloma cells* ,”Annals ofHematology, vol. 64, pp. 132-139
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and Binding Site Topography,” J Mol. Biol., vol. 262, pp. 732-745 charide improves binding to human FcyRJII and antibody-dependent
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homotypic B-cell adhesion,” Biochem J, vol. 361, pp. 431-436 galactose or bisecting N-acetylglucosamnine of human IgG1 com
(2002). plex-type oligosaccharides shows the critical role of enhancing anti
Murphy, et al., “An early response gene (19A) which encodes anovel body-dependent cellular cytotoxicity,” The Journal of Biological
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CD2,” Immunology, Supplement], vol. 60 (1999). Sidorenko, et al., The dual-function CDI50 receptor subfamily: the
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ceptibility to Crohn’ s disease,” Nature, vol. 41 1, pp. 603 -606 (2001). U.S. Appl. No. 13/175,733, ?led Jul. 1,2011.
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action studies,” Blood, vol. 8, No. 11, p. 1 (2006). Appl.No.13/175,751.
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THERAPEUTIC USE OF ANTI-CS1 nol. 169:7-15 (1996); Ogura, Y. et al., Aframeshi? mutation
ANTIBODIES in NOD2 associated with susceptibility to Crohn ’s Disease,
Nature 411: 603-606 (2001).
This application is a continuation of US. patent applica IBDs most often affect the small intestine and colon, but
tion Ser. No. 12/397,026, ?led Mar. 3, 2009, now US. Pat. may involve any portion of the gastrointestinal tract. There
No. 8,088,898, Which is a continuation of US. patent appli are over 1 million people diagnosed With IBD in the United
States alone, With over 10,000 neW cases diagnosed annually.
cation Ser. No. 10/982,357, ?led Nov. 5, 2004, now US. Pat.
Because of the drastic effect in the quality of life for IBD
No. 7,709,610, Which is a continuation in part of US. patent
patients, tens of thousands of lost hours are claimed annually,
application Ser. No. 10/842,011, ?led May 7, 2004, noW
equaling up to 1 billion dollars in missed Work days a year.
abandoned, and claims the bene?t of priority of US. Provi
IBD produces a range of gastrointestinal and extraintesti
sional Application 60/469,211, ?led May 8, 2003, US. Pro
nal symptoms, including diarrhea, rectal bleeding, abdominal
visional Application 60/557,620, ?led Mar. 29, 2004, US.
pain, Weight loss, skin and eye disorders, and delayed groWth
Provisional Application 60/ 557,622, ?led Mar. 29, 2004, and
and sexual maturation in children. TWo types of IBD are
US. ProvisionalApplication 60/557,621, ?led Mar. 29, 2004,
ulcerative colitis and Crohn’s disease, Which share similar
each of Which is speci?cally incorporated herein by reference
symptoms and physiological manifestations, but differ in the
in its entirety. manner in Which they affect the digestive tract. Ulcerative
colitis is characterized by ulcerative in?ammation of all or
FIELD OF THE INVENTION part of the colonic mucosa, most frequently including the
20 rectum. Its symptoms include rectal bleeding and urgency,
The invention relates to the ?eld of antagonists and anti tenesmus, and diarrhea. Ulcerative colitis is accompanied by
bodies in the treatment of diseases, including diseases related serious short- and long-term complications. The most serious
to autoimmune and cancer. The invention further relates to short-term complications are fulminant colitis, toxic mega
methods for detecting, identifying and modulating these dis colon, and perforation. Severe long-term complications
eases. 25 include osteoporosis and colorectal cancer.
Crohn’s disease is a chronic transmural in?ammation that
BACKGROUND OF THE INVENTION may affect any part of the gastrointestinal tract, from the
mouth to the anus. Crohn’s disease is discontinuous, With
Increased expression of immunoglobulin is a characteristic unaffected areas interspersed betWeen one or more involved
of many diseases. High level secretion of immunoglobulin 30 areas. Late in the disease, the mucosa develops a cobblestone
causes a variety of disorders, including hypervisocity syn appearance, Which results from deep longitudinal ulcerations
drome, a debilitating disorder resulting in fatigue, headaches, interlaced With intervening normal mucosa.
shortness of breath, mental confusion, chest pain, kidney Most Crohn’s disease patients present With symptoms of
damage and failure, vision problems and Raynaud’ s phenom abdominal pain and tenderness, chronic or nocturnal diar
enon (poor blood circulation, particularly ?ngers, toes, nose 35 rhea, rectal bleeding, Weight loss, and fever. Crohn’s disease
and ears). Cold agglutinin disease, mixed cryoglobulinemia, evolves over time from a primarily in?ammatory disease into
hypergammaglobulinemia, Sjogren’s syndrome, Lichen one of tWo clinical patterns: stricturing (obstructive) or pen
myxedematosus, and Gaucher’s disease are examples of dis etrating (?stuliZing). In the stricturing form, transmural
eases associated With increased expression of immunoglobu in?ammation produces ?bromuscular proliferation in the
lins. 40 intestinal Wall, folloWed by luminal narroWing. Symptoms of
Increased expression of immunoglobulin targeted to self obstruction become common as CD progresses. In the pen
proteins is a hallmark of autoimmune diseases. Autoimmune etrating form, sinus tracts form as in?ammation tunnels
disease is a failure of the immune system to recogniZe auto through the boWel Wall and breaches the serosal surface,
antigens as self. In autoimmune diseases, the immune system ?stuliZing into adjoining tissues and even through the skin.
mistakenly attacks itself, targeting cells, tissues and organs, 45 Ulcerative colitis and Crohn’s disease are generally diag
eventually resulting in the destruction of physiological sys nosed using clinical, endoscopic, and histologic criteria.
tems. Autoimmunity and autoimmune diseases are multi HoWever, so far the traditional diagnostic techniques have
factorial in origin, With genetic predisposition, host factors established that no single ?nding is absolutely diagnostic for
(e. g., Weakness of immunoregulatory controls, defects in sup one disease or the other. Furthermore, approximately 20% of
pressor T cells, or polyclonal stimulation of B cells resistant 50 patients have a clinical picture that falls betWeen Crohn’s
to controls), environmental factors and antigen-driven disease and ulcerative colitis. Patients that ?t this pro?le are
mechanisms being implicated in the development of autoim said to have indeterminate colitis.
munity and production of self-antibodies to self-antigens. IBD symptoms can greatly impact a patient’s Well-being,
Gastrointestinal disorders and Systemic Lupus Erythrema quality of life, and capacity to function. In?ammatory periods
tosus (SLE) are tWo examples of autoimmune diseases. 55 are protracted and frequent, and depending on the severity,
In?ammatory boWel disease (IBD), a subgroup of gas life crippling. Because IBD is chronic and typically has an
trointestinal disorders, is a group of incurable disorders that onset before 30 years of age, patients generally require life
affect approximately 4 million individuals WorldWide. The long treatment. The elucidation of a role for novel proteins
etiology of recurrent in?ammatory boWel disease is currently and compounds in disease states for identi?cation of potential
unknoWn. Theories include an autoimmune-mediated 60 targets and diagnostic markers is valuable for improving the
destruction of gastrointestinal cells, including lymphocytes. current treatment of in?ammatory boWel disease patients.
Abnormal homotypic aggregation in heritable in?ammatory SLE is characterized by the production of auto-antibodies
boWel disease models has been demonstrated previously, and to a variety of ubiquitous molecules, Which can have patho
mutations in NOD2, a gene implicated in autoimmune disor genic consequences including damage to numerous organs
ders, have been shoWn to predispose patients to Crohn’s 65 and tissues, including skin, kidney, brain, and heart. The
disease. Ni, J. et al., Immunological abnormality in C3H/HeJ current approved treatments for SLE involve non-speci?c
mice with heritable in?ammatory bowel disease, Cell Immu immunosuppression and symptom control through steroids,
US 8,436,146 B2
3 4
immuno suppressive drugs, immunomodulators, and anti -ma approaches 30%, and is the only method knoWn that can cure
larial drugs. However, these treatment approaches result in myelomas. HoWever, for individuals Who are older or cannot
risks of renal toxicity and early mortality. Thus, it is desirable tolerate bone marroW transplantation procedures, chemo
to develop a neW approach that speci?cally interferes With therapy is most appropriate.
lymphocyte activation and auto-antibody production.
Current diagnostic procedures include X rays, bone mar
Other autoimmune diseases in Which increased expression roW aspiration, blood and urine tests (to detect the presence of
of immunoglobulin and/or B cells play a signi?cant role
the Bence Jones protein), and the erythrocyte sedimentation
include idiopathic thrombocytopenia, rheumatoid arthritis
rate assay. Potential cell surface markers in myelomatous
(RA), autoimmune hemolytic anemia, and Myasthenia
plasma cells have also been identi?ed, including CD38, CD9,
gravis. Evidence for the role of B cells and/or increased
CD10, HLA-DR, and CD20. RuiZ-Arugelles G J and San
immunoglobulin comes from studies With patients treated
Miguel J F, Cell Surface Markers in Multiple Myeloma,
With steroids, immunosuppressive agents, and/or anti-CD20
Mayo Clin. Proc. 69:684-90 (1994). Other non-B-cell lineage
antibodies (Which target B cells). Improvement in symptoms
markers include CD2, CD4, CD13, CD14, CD15, CD23, CD
in these diseases correlates With a decrease in B cells and/or
24, CD25, CD33, CD39, CDW40, CD41, CD45R, CD54,
serum immunoglobulin, underscoring the pivotal role that B
cells play in a variety of autoimmune diseases. CD56 and CD71, as Well as unclustered antigens, RI-3, PCA
Increased expression of immunoglobulin can also be seen 1, PCA-2, PC1, 62B1, 8A, 8P6 and MM4). RuiZ-Arugelles,
in malignant diseases. Like autoimmune disorders, the etiol supra; Leo R, et al., Mulliparameler analysis of normal and
ogy of cancer is similarly multi-factorial in origin. Cancer, malignant human plasma cells, Ann. Hematol. 64: 132-9
Which is the second leading cause of death in the United 20 (1992). In addition, appearance of abnormal antibodies,
States, has been linked to mutations in DNA that cause unre knoWn as M-protein, is an indicator of multiple myeloma.
strained groWth of cells. Genetic predisposition plays a large The increased production of M-protein has been linked to
role in the development of many cancers, combined With hyperviscosity syndrome in multiple myelomas, causing
environmental factors, such as smoking and chemical debilitating side effects, including fatigue, headaches, short
mutagenesis. 25 ness of breath, mental confusion, chest pain, kidney damage
Cancer can occur in any tissue or organ of the body. Plasma and failure, vision problems and Raynaud’s phenomenon
cell neoplasms, including multiple myeloma, “Solitary” (poor blood circulation, particularly ?ngers, toes, nose and
myeloma of bone, extramedullary plasmacytoma, plasma cell ears). Cryoglobulinemia occurs When M-protein in the blood
leukemia, macroglobulinemia (including Waldenstrom’s forms particles under cold conditions. These particles can
macroglobulinemia), heavy-chain disease, primary amyloi 30 block small blood vessels and cause pain and numbness in the
dosis, monoclonal gammopathy of unknoWn signi?cance toes, ?ngers, and other extremities during cold Weather. Pro g
(MGUS) are associated With increased expression of immu nostic indicators, such as chromosomal deletions, elevated
noglobulins. Chronic lymphocytic leukemia (CLL), a non levels of beta-2 microglobulin, serum creatinine levels and
plasma cell neoplasm, is also associated With high levels of IgA isotyping have also been studied. Tricot G, et al., Poor
immunoglobulin expression. 35 prognosis in Multiple Myeloma, Blood 86:4250-2 (1995).
Myelomasare tumors of plasma cells derived from a single CS1 (SLAMF7, 19A; Genbank Accession Number
clone, Which typically originates in secondary lymphoid tis NMi021181.3, Ref. Boles and MatheW (2001) Immunoge
sue and then migrates into and resides in bone marroW tissue. netics 52:302-307; Bouchon et al., (2001) J. Immunol. 167:
Myelomas commonly affect the bone marroW and adjacent 5517-5521; Murphy et al., (2002) Biochem. J. 361 :431-436)
bone structures, With primary symptoms of bone pain and 40 is a member of the CD2 subset of the immunoglobulin super
pathological fractures or lesions (osteolytic bone lesions), family. Molecules of the CD2 family are involved in a broad
abnormal bleeding, anemia and increased susceptibility to range of immunomodulatory functions, such as co-activation,
infections. Advanced stages of the disease include renal fail proliferation differentiation, and adhesion of lymphocytes, as
ure, skeletal deformities, compaction of the spinal cord, and Well as immunoglobulin secretion, cytokine production, and
hypercalcemia. Myeloma affects bone cells by inducing 45 NK cell cytotoxicity. Several members of the CD2 family,
osteoclast resorption of bone, hence decimating bone struc such as CD2, CD58, and CD150, play a role or have been
ture and increasing calcium concentration in plasma. The proposed to play a role in a number of autoimmune and
etiology of myelomas is currently unknoWn. Linkage to in?ammatory diseases, such as psoriasis, rheumatoid arthri
radiation damage, mutations in oncogenes, familial causes tis, and multiple sclerosis.
and abnormal IL6 expression have been postulated. 50 CS1 (also knoWn as CRACC, 19A, APEX-1, and FOAP12)
Multiple myelomas are plasma cell tumors With multiple Was isolated and cloned by Boles, K. et al. (see Immunoge
origins. Multiple myelomas account for nearly 10% of all netics 52: 302-307 (2001)). It has been reported that CS1
plasma cell malignancies, and are the most common bone plays a role in NK cell-mediated cytotoxicity and lymphocyte
tumor cancer in adults, With an annual incident rate of 3 to 4 adhesion (Bouchon, A., et al., J. of Immuno. 5517-5521
cases per 100,000 people. In the United States, multiple 55 (2001); Murphy, J. et al., Biochem. J. 361: 431-436 (2002)).
myelomas are the second most common hematologic malig PCT Application PCT/US00/34963 discloses a mono
nancy after Non-Hodgkin’s Lymphoma, With approximately clonal antibody against APEX-l and the use thereof for
50,000 cases in the United States alone, and approximately detecting the produced recombinant extracellular domain of
13,500 neW reported cases every year. The prognosis outlook APEX-1. US. patent application 2003/0113332A1 discloses
for patients diagnosed With multiple myelomas is grim, With 60 monoclonal antibodies against the peptides of natural killer
only several months to a year for patients With advanced cell surface receptors that bind to CS1 and lead to NK cell
forms of the disease. activation. These applications are herein incorporated for ref
Traditional treatment regions for myeloma and multiple erence in its entirety. HoWever, antibodies capable of inhib
myelomas (henceforth referred to as “myeloma”) consist of iting immunoglobulin production by B cells and/or prolifera
chemotherapy, radiation therapy, and surgery. In addition, 65 tion and/or development of myelomas have not been
bone marroW transplantation is recommended for patients developed and disclosed in the above-referenced publica
Who are otherWise in good health. The cure rate for patients tions. Also, evidence of over-expression of CS-1 in autoim
US 8,436,146 B2
5 6
mune disease or cancer has not been developed or disclosed in platelets, red blood cells, endothelial cells (HuVECs), kidney
the above-referenced publications. cells, bronchial airWay cells, small airWay cells, prostate
The elucidation of a role for novel proteins and compounds cells, liver cells or breast cells. CS1 expression is lymphoid
in disease states for identi?cation of potential targets and speci?c, and is detected on cells from patients, including
diagnostic markers is desirable for improving the current plasma cells from multiple myeloma and plasma cell leuke
treatment of autoimmune and cancer patients, including mia patients. Expression is detected only on plasma cells and
patients afflicted with IBD, SLE, RA and myeloma. Accord
not detectable at signi?cant levels on other cell types from
ingly, provided herein are molecular targets for treatment and
bone marroW samples. Accordingly, the present invention has
diagnosis of these diseases, particularly CS1. Additionally,
demonstrated the feasibility of using anti-CS1 antibodies as
provided herein are antagonists that bind to and neutraliZe
therapeutic agents for the treatment of cancer, including but
CS 1, including neutraliZing antibodies such as anti-CS1 anti
not limited to plasma cell neoplasms, including myeloma,
bodies.
multiple myeloma, “solitary” myeloma of bone, extramedul
lary plasmacytoma, plasma cell leukemia, macroglobuline
SUMMARY OF THE INVENTION
mia (including Waldenstrom’s macroglobulinemia), heavy
The present invention provides an antibody or an antigen chain disease, primary amyloidosis, monoclonal
binding fragment that binds to a human CS1 epitope recog gammopathy of unknoWn signi?cance (MGUS). In addition,
niZed by Luc 90. Luc 90 and other antibodies that share the non-plasma cell neoplasms associated With increased expres
same epitope, including Luc 34, Luc 69 and Luc X, are sion of immunoglobulin, including chronic lymphocytic leu
capable of inhibiting immunoglobulin secretion and killing of kemia (CLL), Will also bene?t from anti-CS1 therapy.
CS1 expressing cells. 20 In addition, previous studies have not revealed the expres
The present invention also provides an antibody or an sion of CS1 protein on in vitro PWM (pokeWeed mitogen)
antigen binding fragment that binds to a human CS1 epitope activated peripheral blood B cells, subsets of memory/effec
recogniZed by Luc 63. Luc 63 and other antibodies that share tor versus naive peripheral blood B and T lymphocytes, or
the same epitope, including Luc 4, Luc 12, Luc 23, Luc 29, CD14+ monocytes/macrophages from peripheral blood. Pre
Luc 32 and Luc 37, are capable of inhibiting immunoglobulin 25 vious studies have also not revealed the role of CS1 in immu
secretion and killing of CS1 expressing cells. noglobulin production. As a result, the correlation betWeen
The present invention further provides an antibody or an CS1 and autoimmune diseases has not been previously estab
antigen binding fragment that triggers cytotoxic effects on lished. The present invention is also based in part on our
cells expressing CS1 or enhances cytotoxicity mediated by discovery that the CS1 RNA and protein expression are
immune cells, including ADCC-mediated cytotoxicity of 30 strongly up-regulated in activated peripheral blood B cells,
cells expressing CS1. the cell subset responsible for auto-antibody production and
The present invention ?lrther provides a method for killing believed to play a signi?cant role in the development of
CS1 expressing cells comprising contacting the cells With an autoimmune diseases. Furthermore, the present invention has
effective amount of anti-CS1 antibody. The CS1 expressing revealed that expression of the CS1RNA in SLE patient
cells include plasma cell cancer cells from, e.g., multiple 35 peripheral blood B lymphocytes is increased in comparison to
myeloma, and non-plasma cancer cells from, e.g., chronic B cells from age-matched healthy adults, as Well as in patients
lymphocytic leukemia. The CS1 expressing cells further afflicted with IBD. The present invention reveals that CS-1 is
include leukocytes such as activated B cells or T cells, and expressed on in?ltrating plasma cells in rheumatoid arthritis
leukocytes from patients suffering from SLE and rheumatoid (RA) synovium. The present invention has also revealed that
arthritis. 40 CS1 is involved in antibody production and that antibodies to
The present invention further provides a method for treat CS1 decrease IgM and IgG secreted by B cells from healthy
ing an individual suffering from plasma cell cancers, SLE, adults and patients With lupus. Subsequently, the data of the
rheumatoid arthritis or in?ammatory boWel disease. present invention suggest that CS1 plays an important role in
the establishment of autoimmune diseases, especially SLE,
BRIEF DESCRIPTION OF THE DRAWINGS 45 IBD, and RA. Other diseases associated With an increase in
immunoglobulin, B cells, and/or B cell products Would also
Figures bene?t from anti-CS1 treatment, including cold agglutinin
disease, immunobullous diseases (including bullous pem
FIG. 1A shoWs the inhibition of in vivo human IgG pro phigoid, pemphigus, dermatitis herpetiformis, linear IgA dis
duction in SCID-HuPBMC mouse model by anti-CS1 mono 50 ease, and epidermolysis bullosa acquista), mixed cryoglobu
clonal antibodies. linemia, hypergammaglobulinemia, Sjogren’s syndrome,
FIG. 1B shoWs a comparison of inhibition of in vivo human autoimmune anemia, asthma, myasthenia gravis, multiple
I gG production in SCID-HuPBMC mouse model by anti-CS1 sclerosis, myocardial or pericardial in?ammation, atopic der
monoclonal antibodies Luc 90 and 63. matitis, psoriasis, lichen myxedematosus, and Gaucher’ s dis
FIG. 1C shoWs a summary of the inhibition of in vivo 55 ease.
human IgG production in SCID-HuPBMC mouse model by Moreover, studies have not been conducted before to
anti-CS1 monoclonal antibodies. examine the feasibility of using anti-CS1 antibodies for treat
FIG. 2 shoWs decreased tumor volumes in mouse xeno graft ing autoimmune diseases and plasma cell cancers, including
multiple myeloma models treated With anti-CS1 antibodies myeloma and plasma cell leukemia. An ideal therapeutic
Luc 90 and Luc 63 versus isotype control antibodies. 60 antibody should bind primarily to the target cells. Binding to
FIG. 3 shoWs the effect of anti-CS1 antibodies Luc63 and other cells and tissues can cause potential damage to those
humaniZed Luc63 on OPM-2 tumor groWth in vivo. cells and tissues and/ or deplete the therapeutic antibody so
that an excess amount of the antibody is required to be deliv
DETAILED DESCRIPTION OF THE INVENTION ered to the patient in order to achieve the desired treatment
65 e?icacy. More importantly, an antibody that binds to platelets
The present invention is based in part on our discovery that may have side effects, such as, platelet activation (Which can
there is no signi?cant CS1 protein expression detected on lead to excessive clotting), or platelet depletion (Which can