CN101534860B - Compositions and methods using anti-cs1 antibodies to treat multiple myeloma - Google Patents

Compositions and methods using anti-cs1 antibodies to treat multiple myeloma Download PDF

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CN101534860B
CN101534860B CN200780035366.0A CN200780035366A CN101534860B CN 101534860 B CN101534860 B CN 101534860B CN 200780035366 A CN200780035366 A CN 200780035366A CN 101534860 B CN101534860 B CN 101534860B
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huluc63
ser
leu
treatment
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CN101534860A (en
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D·阿法尔
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AbbVie Biotechnology Ltd
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Facet Biotech Corp
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Abstract

The present invention is directed to pharmaceutical compositions comprising an antibody specif ic for CSl (CD2 subset 1 ), a member of the CD2 family of cell surface glycoproteins, which is highly expressed in myeloma cells, in combination with one or more therapeutic agents. Methods of treating multiple myeloma using said compositions are also the obj ect of the present invention.

Description

Use compositions and the method for anti-cs 1 antibodies to treat multiple myeloma
1. the cross reference of related application
The application requires the patent application serial numbers 60/836,250 submitted on August 7th, 2006 according to 35U.S.C. § 119 (e), and 60/856,144 the priority of submitting on November 1st, 2006, and its content is by with reference to incorporating this paper into.
2. background technology
Multiple myeloma (" MM ") refers to derive from monoclonal plasmacytic malignant proliferation.The term multiple myeloma is used to refer to identical disease interchangeably with myeloma.Myeloma, its product and cause the dysfunction of multiple organ and the symptom of osteodynia or fracture, renal failure, easy infection for the host response of myeloma, anemia, hypocalcemia, and sporadic disorders of hemostasis, the blood vessel performance of neurological symptom and hyperviscosity.Referring to D.Longo, in Harrison ' sPrinciples of Internal Medicine the 14th edition, the 713rd page (McGraw-Hill, New York, 1998).There is no at present the effective long-term treatment method for MM.Myeloma is plasmacytic malignant disease, shows as hyperproteinemia, anemia, renal dysfunction, bone infringement and immunodeficiency.MM is difficult to early diagnosis because the stage may be asymptomatic in early days.If do not provide this disease of any treatment have 6 months median survival interval carry out the sexually transmitted disease (STD) journey.The general chemotherapy is main Therapeutic Method, and be about 3 years with chemotherapeutic median survival interval at present, yet be less than 5% survival of patients and surpass 10 years (referring to Anderson, K. wait the people, AnnualMeeting Report 1999.Recent Advances in the Biology andTreatment of Multiple Myeloma (1999)).
Although multiple myeloma is considered to the drug susceptibility disease, but nearly all patient who at first chemotherapy is responded is finally recurred (referring to Anderson, K. wait the people, AnnualMeeting Report 1999.Recent Advances in the Biology andTreatment of Multiple Myeloma (1999)).Since MM is introduced melphalan and prednisone therapy, test many multiple medicines chemotherapy and comprised vinca alkaloids, anthracycline and based on the treatment of nitroso ureas (referring to Case, the people such as DC (1977) Am.J.Med 63:897903), but on effect, almost do not improve (referring to Case in 30 years of the past, the people such as DC, (1977) Am.J.Med 63:897903; Otsuki, the people such as T., (2000) Cancer Res.60:1).Need new Therapeutic Method, such as the conjoint therapy of the micromolecular inhibitor that uses monoclonal antibody and therapeutic agent and the cell receptor that in MM, involves and/or protein.
3. general introduction
The invention describes compositions and method for the antitumor properties that utilizes anti--CS1 antibody.Can be used for described method and composition anti--CS1 antibody describes in U.S. patent publication No. 2005/0025763 and 2006/0024296, its content is incorporated this paper into by reference.Anti--CS1 antibody target CS1 (CD2-hypotype 1), it also is known as SLAMF7, CRACC, 19A, APEX-1 and FOAP12 (Genbank accession number NM_021181.3).CS1 is the glycoprotein of high expressed in from the patient's who is diagnosed as MM bone marrow sample.In vivo with in vitro study in, anti--CS1 antibody has all shown significant anti-myeloma active (referring to for example U.S. patent publication No. 2005/0025763 and 2006/0024296, its content by with reference to incorporating this paper into).Mode by embodiment, but be not limited to this, anti--CS1 antibody, HuLuc63 via antibody dependent cellular cytotoxicity (ADCC) effectively mediate the myeloma cell the molten effect of born of the same parents (referring to, for example, U.S. patent publication No. 2005/0025763, and its content is incorporated this paper into by reference).In the tumor model of myeloma mice, with HuLuc63 treatment the tumor body is significantly dwindled surpass 50% (referring to, for example, U.S. patent publication No. 2005/0025763, its content is by with reference to incorporating this paper into).
The present invention relates to be used for the treatment of and be diagnosed as the uncertain MG of meaning (Monoclonal Gammopathy of Undetermined Significance, MGUS), smoulder the patient's of type myeloma, asymptomatic MM and Symptomatic MM compositions and method, scope from new diagnosis to late recurrent/intractable myeloma.Particularly, the method relates to giving of pharmaceutical composition, the associating of described pharmaceutical composition comprises anti--CS1 antibody and one or more therapeutic agents.Anti--CS1 antibody typically gives with the dosage intravenous of scope from 0.5 to 20mg/kg, and is weekly to per month once.
One or more therapeutic agents such as targeting preparation, traditional chemotherapeutics, hormone therapy agent and supportive care agent and/or its combination, can resist-CS1 antibody in, before or after give.Described medicament can separately give or be combined in the intermixture and give as single compositions together.Described compositions can any known mode in this area give.
In certain embodiments, pharmaceutical composition described herein has improved the sensitivity of multiple myeloma cells to therapeutic agent.For example, anti--CS1 antibody such as HuLuc63 comprises the activity that improves therapeutic agent, so that lower dosage can be used in compositions as herein described and the method.
In certain embodiments, pharmaceutical composition described herein causes at least a useful reaction according to the definition of European blood and bone marrow transplantation tissue (EBMT).For example pharmaceutical composition described herein give can cause complete reaction, partial reaction, minimal reaction, unchanged or plateau (plateau).
4. description of drawings
Fig. 1 has described alone HuLuc63 and has united anti-tumor activity in the mice multiple myeloma heteroplastic transplantation model in vivo with dexamethasone,
Fig. 2 has described alone HuLuc63, alone Thalidomide, and HuLuc63 and Thalidomide unite the anti-tumor activity in the mice multiple myeloma heteroplastic transplantation model in vivo,
Fig. 3 has described alone HuLuc63, Thalidomide/dexamethasone, and HuLuc63 and Thalidomide and dexamethasone unite the anti-tumor activity in the mice multiple myeloma heteroplastic transplantation model in vivo, and
Fig. 4 has described alone HuLuc63 and has united anti-tumor activity in the mice multiple myeloma heteroplastic transplantation model in vivo with bevacizumab (Bevacizumab).
5. detailed Description Of The Invention
Compositions as herein described will resist-and CS1 antibody and one or more therapeutic agents unite to strengthen with given dose or to replenish mutual anti-myeloma active.Be fit to anti--example of CS1 antibody comprises, but be not limited to this, in conjunction with the separated antibody of one or more three antigenic determinants that identify at CS1 and the monoclonal antibody that is produced by hybridoma cell line: Luc2, Luc3, Luc15, Luc22, Luc23, Luc29, Luc32, Luc34, Luc35, Luc37, Luc38, Luc39, Luc56, Luc60, Luc63, Luc69, LucX.1, LucX.2 or Luc90.Hereinafter these monoclonal antibodies are called antibody: Luc2, Luc3, Luc15, Luc22, Luc23, Luc29, Luc32, Luc34, Luc35, Luc37, Luc38, Luc39, Luc56, Luc60, Luc63, Luc69, LucX and Luc90.The humanization form is by prefix " hu " expression (referring to, U.S. patent publication No. 2005/0025763 and 2006/0024296 for example, its content by with reference to incorporating this paper into).
In certain embodiments, be fit to anti--CS1 antibody comprises separated antibody (SEQ ID NO:1, the following table 1 in conjunction with one or more three antigenic determinants that identify at CS1; Referring to for example U.S. patent publication No. 2006/0024296, its content is incorporated this paper into by reference).As disclosed and following as shown in the table 1 in U.S. patent publication No. 2006/0024296, the CS1 antibody combining site is divided into 3 antigenic determinants:
(1) epitope of being determined by Luc90, it is in conjunction with hu50/mu50 (SEQ IDNO:2).This epitope has been contained certainly about amino acid residue 23 of people CS1 to about amino acid residue 151.This epitope is positioned at the domain 1 (V domain) of extracellular domain.This epitope is also by Luc34, LucX (comprising LucX.1 and LucX.2) and Luc69 identification.
(2) epitope of being determined by Luc38, it is in conjunction with mu25/hu75 (SEQ IDNO:3) and hu50/mu50 (SEQ ID NO:81).This epitope may have been contained certainly about amino acid residue 68 of people CS1 to about amino acid residue 151.This epitope is also identified by Luc5.
(3) epitope of being determined by Luc63, it is in conjunction with mu75/hu25 (SEQ IDNO:4).This epitope has been contained certainly about amino acid residue 170 of people CS1 to about amino acid residue 227.This epitope is positioned at the domain 2 (C2 domain) of people CS1.This epitope is also by Luc4, Luc12, Luc23, Luc29, Luc32 and Luc37 identification.
Described method and will touching upon in detail below the pharmaceutical composition, but typically comprise at least a aforesaid anti--CS1 antibody.In certain embodiments, described pharmaceutical composition comprises anti--CS1 antibody HuLuc63.HuLuc63 is for pointing to the humanization recombinant monoclonal IgG1 antibody of people CS1.The aminoacid sequence of the variable region of heavy chain of HuLuc63 (SEQ ID NO:5) and variable region of light chain (SEQID NO:6) is open in U.S. patent publication No. 2005/0025763, and its content is incorporated this paper into by reference, and in the typing table 1.
Table 1
SEQ ID NO： Aminoacid sequence
SEQ ID NO：1 Met Ala Gly Ser Pro Thr Cys Leu Thr Leu Ile Tyr Ile Leu Trp Gln Leu Thr Gly Ser Ala Ala Ser Gly Pro Val Lys Glu Leu Val Gly Ser Val Gly Gly Ala Val Thr Phe Pro Leu Lys Ser Lys Val Lys Gln Val Asp Ser Ile Val Trp Thr Phe Asn Thr Thr Pro Leu Val Thr Ile Gln Pro Glu Gly Gly Thr Ile Ile Val Thr Gln Asn Arg Asn Arg Glu Arg Val Asp Phe Pro Asp Gly Gly Tyr Ser Leu Lys Leu Ser Lys Leu Lys Lys Asn Asp Ser Gly Ile Tyr Tyr Val Gly Ile Tyr Ser Ser Ser Leu Gln Gln Pro Ser Thr Gln Glu Tyr Val Leu His Val Tyr Glu His Leu Ser Lys Pro Lys Val Thr Met Gly Leu Gln Ser Asn Lys Asn Gly Thr Cys Val Thr Asn Leu Thr Cys Cys Met Glu His Gly Glu Glu Asp Val Ile Tyr Thr Trp Lys Ala Leu Gly Gln Ala Ala Asn Glu Ser His Asn Gly Ser Ile Leu Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr Phe Ile Cys Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser Pro Ile Leu Ala Arg Lys Leu Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser Ser Met Val Leu Leu Cys Leu Leu Leu Val Pro Leu Leu Leu Ser Leu Phe Val Leu Gly Leu Phe Leu Trp Phe Leu Lys Arg Glu Arg Gln Glu Glu Tyr Ile Glu Glu Lys Lys Arg Val Asp Ile Cys Arg Glu Thr Pro Asn Ile Cys Pro His Ser Gly Glu Asn Thr Glu Tyr Asp Thr Ile Pro His Thr Asn Arg Thr Ile Leu Lys Glu Asp Pro Ala Asn Thr Val Tyr Ser Thr Val Glu Ile Pro Lys Lys Met Glu Asn Pro His Ser Leu Leu Thr Met Pro Asp Thr Pro Arg Leu Phe Ala Tyr Glu Asn Val Ile
SEQ ID NO：2 Met Ala Gly Ser Pro Thr Cys Leu Thr Leu Ile Tyr Ile Leu Trp Gln Leu Thr Gly Ser Ala Ala Ser Gly Pro Val Lys Glu Leu Val Gly Ser Val Gly Gly Ala Val Thr Phe Pro Leu Lys Ser Lys Val Lys Gln Val Asp Ser Ile Val Trp Thr Phe Asn Thr Thr Pro Leu Val Thr Ile Gln Pro Glu Gly Gly Thr Ile Ile Val Thr Gln Asn Arg Asn Arg Glu Arg Val Asp Phe Pro Asp Gly Gly Tyr Ser Leu Lys Leu Ser Lys Leu Lys Lys Asn Asp Ser Gly Ile Tyr Tyr Val Gly Ile Tyr Ser Ser Ser Leu Gln Gln Pro Ser Thr Gln Glu Tyr Val Leu His Val Tyr Glu His Leu Ser Lys Pro Lys Val Thr Ile Asp Arg Gln Ser Asn Lys Asn Gly Thr Cys Val Ile Asn Leu Thr
SEQ ID NO： Aminoacid sequence
Cys Ser Thr Asp Gln Asp Gly Glu Asn Val Thr Tyr Ser Trp Lys Ala Val Gly Gln Gly Asp Asn Gln Phe His Asp Gly Ala Thr Leu Ser Ile Ala Trp Arg Ser Gly Glu Lys Asp Gln Ala Leu Thr Cys Met Ala Arg Asn Pro Val Ser Asn Ser Phe Ser Thr Pro Val Phe Pro Gln Lys Leu Cys Glu Asp Ala Ala Thr Asp Leu Thr Ser Leu Arg Gly
SEQ ID NO：3 Met Ala Arg Phe Ser Thr Tyr Ile Ile Phe Thr Ser Val Leu Cys Gln Leu Thr Val Thr Ala Ala Ser Gly Thr Leu Lys Lys Val Ala Gly Ala Leu Asp Gly Ser Val Thr Phe Thr Leu Asn Ile Thr Glu Ile Lys Val Asp Tyr Val Val Trp Thr Phe Asn Thr Phe Phe Leu Ala Met Val Lys Lys Asp Gly Gly Thr Ile Ile Val Thr Gln Asn Arg Asn Arg Glu Arg Val Asp Phe Pro Asp Gly Gly Tyr Ser Leu Lys Leu Ser Lys Leu Lys Lys Asn Asp Ser Gly Ile Tyr Tyr Val Gly Ile Tyr Ser Ser Ser Leu Gln Gln Pro Ser Thr Gln Glu Tyr Val Leu His Val Tyr Glu His Leu Ser Lys Pro Lys Val Thr Met Gly Leu Gln Ser Asn Lys Asn Gly Thr Cys Val Thr Asn Leu Thr Cys Cys Met Glu His Gly Glu Glu Asp Val Ile Tyr Thr Trp Lys Ala Leu Gly Gln Ala Ala Asn Glu Ser His Asn Gly Ser Ile Leu Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr Phe Ile Cys Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser Pro Ile Leu Ala Arg Lys Leu Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser Ser Met Val
SEQ ID NO：4 Met Ala Arg Phe Ser Thr Tyr Ile Ile Phe Thr Ser Val Leu Cys Gln Leu Thr Val Thr Ala Ala Ser Gly Thr Leu Lys Lys Val Ala Gly Ala Leu Asp Gly Ser Val Thr Phe Thr Leu Asn Ile Thr Glu Ile Lys Val Asp Tyr Val Val Trp Thr Phe Asn Thr Phe Phe Leu Ala Met Val Lys Lys Asp Gly Val Thr Ser Gln Ser Ser Asn Lys Glu Arg Ile Val Phe Pro Asp Gly Leu Tyr Ser Met Lys Leu Ser Gln Leu Lys Lys Asn Asp Ser Gly Ala Tyr Arg Ala Glu Ile Tyr Ser Thr Ser Ser Gln Ala Ser Leu Ile Gln Glu Tyr Val Leu His Val Tyr Lys His Leu Ser Arg Pro Lys Val Thr Ile Asp Arg Gln Ser Asn Lys Asn Gly Thr Cys Val Ile Asn Leu Thr Cys Ser Thr Asp Gln Asp Gly Glu Asn Val Thr Tyr Ser Trp Lys Ala Val Gly Gln Ala Ala Asn Glu Ser His Asn Gly Ser Ile Leu Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr Phe Ile Cys Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser Pro Ile Leu Ala Arg Lys Leu Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser Ser Met Val
SEQ ID NO：5 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
SEQ ID NO： Aminoacid sequence
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
SEQ ID NO：6 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
Under some dosage, observe additive effect, under other dosage, observe cooperative effect.In certain embodiments, described cooperative effect allows one or more therapeutic agents and the antibody combined dosage with minimizing of one or more anti--CS1 to give, and still keeps usefulness.If the side effect relevant with using these medicaments is dose dependent, the then use of compositions as herein described and method, can reduce in the tradition that is used for the treatment of MM and new therapeutic scheme the harmful side effect of observing with recommended dose when these medicaments.
In other embodiments, cooperative effect allows one or more therapeutic agents and one or more, and anti--CS1 antibody is united with approval dosage and is given, but has the usefulness that is higher than expection.
Can give that described compositions is used for treating the uncertain MG of meaning (MGUS), smoulders the type myeloma, asymptomatic MM and Symptomatic MM, scope from new diagnose out to late recurrent/obstinate myeloma.Typically, give described compositions and cause the minimizing of M-albumen in serum or the urine so that observe the plateau that defined by European blood and bone marrow transplantation tissue (EBMT), unchanged, minimal reaction, partial reaction or complete reaction.
5.2 pharmaceutical composition
Provide to be beneficial at this and tumor body among patient who is diagnosed as multiple myeloma is dwindled and/or pharmaceutical composition that tumor growth is degenerated.In addition, this pharmaceutical composition can be used for the treatment of to have m protein (M albumen, paraprotein) be the disease of feature in serum or the urine.
In certain embodiments, the different component of described compositions provides dividually.For example, anti--CS1 antibody can provide in the first pharmaceutical composition, and therapeutic agent can provide in the second compositions.If described compositions comprises two or more therapeutic agents, anti--CS1 antibody can provide in the first pharmaceutical composition, and a kind of therapeutic agent can provide in the second compositions and another kind of therapeutic agent can provide in the third compositions.In other embodiments, anti--CS1 antibody can provide in a kind of pharmaceutical composition and therapeutic agent can be combined in the second pharmaceutical composition and provides.In other other embodiment, can provide a kind of compositions that comprises anti--CS1 antibody and the associating of one or more therapeutic agents.
In typical embodiment, anti--CS1 antibody is enough to allow the pharmaceutical composition with 0.5mg/kg to 20mg/kg intravenous administration to exist with concentration.Be suitable in certain embodiments resisting in described compositions and the method-CS1 antibody concentration and comprise, but be not limited to this, at least about 0.5mg/kg, at least about 0.75mg/kg, at least about 1mg/kg, at least about 2mg/kg, at least about 2.5mg/kg, at least about 3mg/kg, at least about 4mg/kg, at least about 5mg/kg, at least about 6mg/kg, at least about 7mg/kg, at least about 8mg/kg, at least about 9mg/kg, at least about 10mg/kg, at least about 11mg/kg, at least about 12mg/kg, at least about 13mg/kg, at least about 14mg/kg, at least about 15mg/kg, at least about 16mg/kg, at least about 17mg/kg, at least about 18mg/kg, at least about 19mg/kg, and at least about 20mg/kg.
Anti--CS1 antibody can single dose or the multiple dose scheme give.Usually, anti--CS1 antibody gave to about 24 hours time period at certainly about 1 hour, but typically gave within about 1 to 2 hour time period.Dosage can repeat about 1 thoughtful about 4 weeks or longer time, altogether 4 doses or multi-agent more.Typically, dosage repeats weekly once, repeat once week about, or per month once, minimum 4 doses to maximum 52 doses.
With the effective dose of anti--CS1 Antybody therapy, total agent number and the length for the treatment of time determine be in those skilled in the art's limit of power, and dose escalation study that can Application standard measure maximum tolerated dose (MTD) determine (referring to, such as people such as Richardson, 2002, Blood, 100 (9): 3063-3067, its content is incorporated this paper into by reference).
In certain embodiments, one or more therapeutic agents with anti--CS1 is antibody combined to be given.Described medicament can resist-CS1 antibody in, before or after give.
In certain embodiments, anti--CS1 antibody gave before giving therapeutic agent.For example anti--CS1 antibody can be before giving therapeutic agent gives in about 0 to 60 day.In certain embodiments, anti--CS1 antibody is such as HuLuc63, before giving therapeutic agent about 30 minutes to about 1 hour, or before giving therapeutic agent about 1 hour to about 2 hours, or before giving therapeutic agent about 2 hours to about 4 hours, or before giving therapeutic agent about 4 hours to about 6 hours, or before giving therapeutic agent about 6 hours to about 8 hours, or before giving therapeutic agent about 8 hours to about 16 hours, or before giving therapeutic agent about 16 hours to 1 day, or before giving therapeutic agent about 1 to 5 day, or before giving therapeutic agent about 5 to 10 days, or before giving therapeutic agent about 10 to 15 days, or before giving therapeutic agent about 15 to 20 days, or before giving therapeutic agent about 20 to 30 days, or before giving therapeutic agent about 30 to 40 days and before giving therapeutic agent, gave in about 40 to 50 days, or before giving therapeutic agent, gave in about 50 to 60 days.
In certain embodiments, when giving therapeutic agent, resist-CS1 antibody.
In certain embodiments, after giving therapeutic agent, resist-CS1 antibody.For example, anti--CS1 antibody is such as HuLuc63, can be after giving therapeutic agent gives in about 0 to 60 day.In certain embodiments, HuLuc63 after giving therapeutic agent about 30 minutes to about 1 hour, or after giving therapeutic agent about 1 hour to about 2 hours, or after giving therapeutic agent about 2 hours to about 4 hours, after giving therapeutic agent about 4 hours to about 6 hours, or after giving therapeutic agent about 6 hours to about 8 hours, or after giving therapeutic agent about 8 hours to about 16 hours, or after giving therapeutic agent about 16 hours to 1 day, or after giving therapeutic agent about 1 day to 5 days, or after giving therapeutic agent about 5 days to 10 days, or after giving therapeutic agent about 10 days to 15 days, or after giving therapeutic agent about 15 days to 20 days, or after giving therapeutic agent about 20 days to 30 days, or after giving therapeutic agent about 30 days to 40 days, or after giving therapeutic agent about 40 days to 50 days, or after giving therapeutic agent, gave in about 50 days to 60 days.
Can comprise with the therapeutic agent of the antibody combined use of anti-CS-1 as herein described targeting preparation, traditional chemotherapeutics, hormone therapy agent and supportive care agent, but be not limited to this.One or more different classes of therapeutic agents, for example targeting preparation, traditional chemotherapeutics, hormone and supportive care agent and/or subclass can be combined in the compositions as herein described.As herein describedly different classes ofly can further be categorized as subclass.For example, depend on the mechanism of action, targeting preparation can be divided into many different subclasses.Be apparent that for those skilled in the art, described medicament can have more than a kind of mechanism of action and therefore can be divided into one or more subclasses, for purpose as herein described, be divided into following subclass: anti-angiogenic agent, growth factor signal inhibitor peptides, immunomodulator, protein synthesis, folding and/or degradation inhibitor, gene expression inhibitor, short apoptosis agent, the medicament of Inhibitory signal conduction and the medicament with " other " mechanism of action.Typically, it is unknown or characterize deficiently to belong to the mechanism of action of medicament of " other " subclass.
For example, in certain embodiments, targeting preparation, such as bevacizumab, Sutinib, Sorafenib, 2ME2 or 2ME2, finasunate, PTK787, ZD6474, VEGF Trap (aflibercept), volt Lip river former times monoclonal antibody, Yi Ruixi pearl (etaracizumab) (MEDI-522), cilengitide, erlotinib, Cetuximab, Victibix, gefitinib, Herceptin, TKI258, CP-751,871, A Saixipu (atacicept), Rituximab, A Lun pearl monoclonal antibody, aldesleukin, atlizumab, holder pearl monoclonal antibody, CCI-779, everolimus, NPI-1387, MLNM3897, HCD122, SGN-40, HLL1, huN901-DM1, Atiprimod, natalizumab, bortezomib, carfilzomib, NPI-0052, KOS-953 (tanespimycin), saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, LBH589, horse handkerchief wood monoclonal antibody, come husky wooden monoclonal antibody, AMG951, ABT-737, Ao Limeisheng, Puli's peptide is new, SCIO-469, P276-00, grace is pricked the cry loudly woods, Zarnestra, perifosine, imatinib, Dasatinib, lenalidomide, Thalidomide, simvastatin, and celecoxib can and be used for the treatment of MM patient with anti--CS1 antibody such as HuLuc63 associating.
In the mode of other example, traditional chemotherapeutics, such as alkylating agent (for example, oxaliplatin, carboplatin, cisplatin, cyclophosphamide, melphalan, ifosfamide, uracil mustard, chlorambucil, carmustine, mechloethamine, thio-tepa, sulphur butane, the temozolomide, dacarbazine), antimetabolite is (for example, gemcitabine, cytosine arabinoside, ara-C, capecitabine, 5FU (5-fluorouracil), azathioprine, mercaptopurine (6-MP), 6-thioguanine, aminopterin, pemetrexed, methotrexate), plant alkaloid and terpenoid are (for example, Docetaxel, taxol, vincristine, vinblastine, vinorelbine, vindesine, etoposide, VP-16, teniposide, irinotecan, topotecan), antitumor antibiotics (for example, actinomycin D, doxorubicin, the liposome doxorubicin, daunorubicin, daunomycin, epirubicin, mitoxantrone, doxorubicin, bleomycin, plicamycin, ametycin, carminomycin, the Ai Sibo mycin), and other medicament (for example darinaparsin) can and be used for the treatment of MM with anti--CS1 antibody such as HuLuc63 associating.
In the mode of other example, hormone preparation is such as Anastrozole, letrozole, and goserelin, tamoxifen, dexamethasone, prednisone, and prednisilone can and be used for the treatment of MM with anti--CS1 antibody such as HuLuc63 associating.
In the mode of other example, the supportive care agent is such as handkerchief agate diphosphonic acid, zoledronic acid, ibandronate, Ganite (Fujisawa)., ground Shu Dankang, darbepoetin α, recombinant human erythropoietin α, eltrombopag olamine, and the Pei Feisi booth can and be used for the treatment of MM with anti--CS1 antibody such as HuLuc63 associating.
Therapeutic agent can think that suitable mode administration also typically provides with common received effective dosage ranges with any clinician, such as at Physician Desk Reference, the 56th edition (2002), Publisher Medical Economics, those that describe among the New Jersey.In other embodiments, can the implementation criteria dosage escalation determine maximum tolerated dose (MTD) (referring to, for example, Richardson waits the people, 2002, Blood, 100 (9): 3063-3067, its content is by with reference to incorporating this paper into).
In certain embodiments, can use the dosage of the common received effective dose that is lower than therapeutic agent.For example, in different embodiments, the dosage that described compositions comprises is lower than about 10% to 75% of common received effective dosage ranges.In certain embodiments, use common received effective dosage ranges at least about 10% or lower, at least about 15% or lower, at least about 25%, at least about 30% or lower, at least about 40% or lower, at least about 50% or lower, at least about 60% or lower, at least about 75% or lower, and at least about 90%.
Therapeutic agent can give separately or in succession give, or gives with the intermixture with other therapeutic agent, as following.Described therapeutic agent can orally give, intravenous gives, general ground by injection in muscle, subcutaneous, sheath or intraperitoneal give.
In certain embodiments, the therapeutic agent that provides in described pharmaceutical composition is selected from lower group: dexamethasone, Thalidomide, vincristine, carmustine (BCNU), melphalan, cyclophosphamide, prednisone, doxorubicin, cisplatin, rely on uncle's glycosides, bortezomib, lenalidomide, cytosine arabinoside (ara-C), and/or its combination.
Yet in certain embodiments, described pharmaceutical composition does not comprise bortezomib and/or lenalidomide.
Correspondingly, in certain embodiments, provide two kinds of pharmaceutical compositions: the first comprise the treatment effective dose anti--CS1 antibody is such as HuLuc63, and the second comprises the dexamethasone for the treatment of effective dose.
In certain embodiments, provide at least two kinds of pharmaceutical compositions: the first comprise the treatment effective dose anti--CS1 antibody is such as HuLuc63, and the second comprises dexamethasone and the Thalidomide for the treatment of effective dose.In certain embodiments, dexamethasone and Thalidomide provide dividually, so that altogether three kinds of pharmaceutical compositions are provided: the first comprises anti--CS1 antibody such as HuLuc63, and the second comprises dexamethasone and the third comprises Thalidomide.
In certain embodiments, provide at least two kinds of pharmaceutical compositions: the first comprises resisting-CS1 antibody for the treatment of effective dose, comprises vincristine, doxorubicin and the dexamethasone (for example VAD) for the treatment of effective dose such as HuLuc63 and the second.In certain embodiments, vincristine, doxorubicin and dexamethasone provide dividually.If described medicament still keeps their usefulness, can prepare the compositions that comprises other combination, depend in part on dosage, route of administration, and described medicament is to provide with solid, semisolid or liquid form.For example can prepare altogether three kinds of pharmaceutical compositions: the first comprises resisting-CS1 antibody for the treatment of effective dose, and such as HuLuc63, the second comprises dexamethasone, and the third comprises vincristine and doxorubicin.
At least two kinds of pharmaceutical compositions are provided in certain embodiments: the first comprises resisting-CS1 antibody for the treatment of effective dose, such as HuLuc63, and the second comprises doxorubicin HCl lipidosome injection, vincristine and the dexamethasone (for example DVd) for the treatment of effective dose.If described medicament still keeps their usefulness, can prepare the compositions that comprises other combination, depend in part on dosage, route of administration, and described medicament is to provide with solid, semisolid or liquid form.Can prepare altogether three kinds of pharmaceutical compositions: the first comprises resisting-CS1 antibody for the treatment of effective dose, and such as HuLuc63, the second comprises doxorubicin hydrochloride liposome injection, and the third comprises vincristine and dexamethasone.
In certain embodiments, provide two kinds of pharmaceutical compositions: the first comprise the treatment effective dose anti--CS1 antibody comprises the cyclophosphamide for the treatment of effective dose such as HuLuc63 and the second.
In certain embodiments, at least two kinds of pharmaceutical compositions are provided: the first comprise the treatment effective dose anti--CS1 antibody is such as HuLuc63, and the second comprises dexamethasone, Thalidomide, cisplatin, doxorubicin, cyclophosphamide and the etoposide (for example DT-PACE) for the treatment of effective dose.If described medicament still keeps their usefulness, can prepare the compositions that comprises other combination, depending in part on dosage, route of administration and described medicament is to provide with solid, semisolid or liquid form.For example, dexamethasone and Thalidomide can provide in a kind of compositions, and cisplatin, doxorubicin, cyclophosphamide and etoposide provide in another kind of compositions.
In certain embodiments, provide at least two kinds of pharmaceutical compositions: the first comprises resisting-CS1 antibody for the treatment of effective dose, and such as HuLuc63, and the second comprises vincristine, doxorubicin, dexamethasone and the cyclophosphamide for the treatment of effective dose.If described medicament still keeps their usefulness, then can prepare the compositions that comprises other combination, depend in part on dosage, route of administration, and described medicament is to provide with solid, semisolid or liquid form.For example, vincristine, doxorubicin and cyclophosphamide can be used as a kind of compositions and provide, and dexamethasone is as the second.
In certain embodiments, provide at least two kinds of pharmaceutical compositions: the first comprise the treatment effective dose anti--CS1 antibody comprises doxorubicin HCl lipidosome injection, vincristine, dexamethasone and the Thalidomide for the treatment of effective dose such as HuLuc63 and the second.If described medicament still keeps their usefulness, can prepare the compositions that comprises other combination, depend in part on dosage, route of administration, and described medicament is to provide with solid, semisolid or liquid form.For example, vincristine, dexamethasone and Thalidomide can be used as a kind of compositions provides with doxorubicin HCl lipidosome injection as the second.
In certain embodiments, provide at least two kinds of pharmaceutical compositions: the first comprise the treatment effective dose anti--CS1 antibody comprises doxorubicin HCl lipidosome injection and the bortezomib for the treatment of effective dose such as HuLuc63 and the second.If described medicament still keeps their usefulness, can prepare the compositions that comprises other combination, depend in part on dosage, route of administration, and described medicament is to provide with solid, semisolid or liquid form.For example, doxorubicin HCl lipidosome injection can be used as a kind of compositions provides with bortezomib as the second.
In certain embodiments, in pharmaceutical composition as herein described, can provide the medicament with mechanism of action identical with anti-CS 1 antibodies, such as HuMax-Cd38 (Genmab).
In certain embodiments, described pharmaceutical composition comprises the therapeutic agent with the mechanism of action that is different from anti--CS1 antibody.The targeting preparation that for example suppresses angiogenesis, but comprise and being not limited to: bevacizumab, sutinib, Sorafenib, 2ME2 or 2ME2, finasunate, PTK787, ZD6474, VEGF Trap, volt Lip river former times monoclonal antibody, Yi Ruixi pearl (MEDI-522), can be used in the pharmaceutical composition as herein described cilengitide.In other embodiments, the medicament that suppresses the growth factor signal peptide comprises, but is not limited to: erlotinib, Cetuximab, Victibix, gefitinib, Herceptin, TKI258, CP-751,871, A Saixipu (atacicept) can be used in the compositions as herein described.In other embodiments, immunomodulator comprises, but is not limited to: Rituximab, A Lun pearl monoclonal antibody, aldesleukin, atlizumab, holder pearl monoclonal antibody, CCI-779, everolimus, NPI-1387, MLNM3897, HCD122, SGN-40, HLL1, huN901-DM1, Atiprimod, natalizumab can be used in the pharmaceutical composition as herein described.In other embodiments, the medicament that Profilin matter is synthesized, folded or degrade comprises, but is not limited to: bortezomib, carfilzomib, NPI-0052, KOS-953, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate can be used in the compositions as herein described.In other embodiments, the medicament of inhibition of gene expression comprises, but is not limited to: belinostat, LBH589 can be used in the compositions as herein described.In other embodiments, short apoptosis agent comprises, but is not limited to: horse handkerchief wood monoclonal antibody, come husky wooden monoclonal antibody, and AMG951, ABT-737, Ao Limeisheng, Puli's peptide is new, can be used in the compositions as herein described.In other embodiments, the medicament of Inhibitory signal conduction comprises, but is not limited to: SCIO-469, and P276-00, grace is pricked the cry loudly woods, Zarnestra, perifosine, imatinib can be used in the compositions as herein described.In other embodiments, the medicament with other mechanism of action comprises, but is not limited to: Dasatinib, and lenalidomide, Thalidomide, simvastatin, and celecoxib can be used in the compositions as herein described.
Described pharmaceutical composition can solid, semisolid or liquid medicine dosage form (for example, suspensoid or aerosol) exist.Typically, described compositions gives with the unit dosage forms of the single-dose that is suitable for exact dose.For example anti--CS1 antibody can scope from about dose package of 1 to 1000mg.In certain embodiments, anti--CS1 antibody can dosage at least about 1mg, at least about 10mg, at least about 20mg, at least about 50mg, at least about 100mg, at least about 200mg, at least about 300mg, at least about 400mg, at least about 500mg, at least about 750mg, pack at least about 1000mg.
Described compositions can also comprise, depends on desirable preparation, the acceptable non-toxic carrier of medicine or diluent, and it is defined as the excipient that is generally used for preparing for the pharmaceutical composition of animal or human's administration.Select diluent take the biological activity that do not affect compositions as purpose.The example of this diluent is distilled water, normal saline, Ringer ' s solution, glucose solution and Hank ' s solution.
In addition, described pharmaceutical composition or preparation can also comprise stabilizing agent of other carrier, adjuvant or nontoxic, non-therapeutic, non-immunogenic etc.The effective dose of this diluent or carrier is for effectively obtaining those amounts at the dissolubility of component or the acceptable preparation of medicine aspect the biological activity.
5.3 use described medicine composite for curing multiple myeloma
Pharmaceutical composition as herein described is used for the treatment of MM.The described compositions patient that can be used for the treatment of the uncertain MG of meaning (MGUS), smoulder type myeloma, asymptomatic MM and Symptomatic MM typically, scope from new diagnosis to late recurrent/intractable myeloma.
Described compositions can be combined with other treatment measure, for example, autologous stem cell transplantation and allogenic effector lymphocyte transplant, develop based on the treatment myeloma effective treatment measure by stages (referring to, Multiple Myeloma Research Foundation for example, MultipleMyeloma:Stem Cell Transplantation 1-30 (2004); U.S.PatentNos.6,143,292, and 5,928,639, Igarashi waits the people, and Blood 2004,104 (1): 170-177, Maloney waits the people, and 2003, Blood, 102 (9): 3447-3454, Badros waits the people, 2002, J Clin Oncol., 20:1295-1303, Tricot, Deng the people, 1996, Blood, 87 (3): 1196-1198; Its content is incorporated this paper into by reference).
The Staging System of extensive employing is the Durie-Salmon system since 1975, wherein the clinical stages of disease (I phase, II phase, or the III phase) based on four measurement indexs (referring to, Durie and Salmon for example, 1975, Cancer, 36:842-854).These four measurement indexs are: the level (being also referred to as paraprotein) of monoclonal (M) albumen in (1) serum and/or the urine; (2) quantity of osteolytic lesion; (3) Hemoglobin Value and (4) serum calcium level.Can be with these three phase Further Divisions according to renal function, be categorized as A (relatively normal renal function, serum creatinine value＜2.0mg/dL) and B (unusual renal function, kreatinin value 〉=2.0mg/dL).New simpler be chosen as International Staging System (ISS) (referring to, such as people such as Greipp, 2003, " Development of aninternational prognostic index (IPI) for myeloma:report of theinternational myeloma workingg roup ", The Hematology).ISS is based on two blood testing results of assessment, β 2-microglobulin (β 2-M) and albumin, it is divided into three the prognosis groups irrelevant with the treatment type with the patient.
Give pharmaceutical composition with the dosage range selected and approach and typically cause the useful reaction that is defined by European blood and bone marrow transplantation tissue (EBMT).Table 2 has been listed the EBMT standard for reaction.
Figure G2007800353660D00161
1EBMT: European blood and bone marrow transplantation tissue; IBMTR: IBMTR; ABMTR: autoblood and bone marrow transplantation registry.
2Only for the patient who suffers from the non-secretory myeloma, require the bone marrow mesoplasmatocyte reduce original amount＞25-49% (minimal reaction) of 50% (partial reaction) or original amount.
3In the non-secretory myeloma, bone marrow plasma cell absolute value should increase＞and 25% and at least 10%; MRI checks that possibility is helpful in the patient who selects.
The additional standard that can be used for weighing therapeutic effect comprises " near complete reaction " and " extraordinary partial reaction "." near complete reaction " is according to " complete reaction " standard definition (CR), but the immunofixation test is positive." extraordinary partial reaction " be defined as M albumen reduce to surpass 90% (referring to, Multiple Myeloma ResearchFoundation for example, Multiple Myeloma:Treatment Overview 9 (2005)).
Show clinically in the individuality of at least a symptom relevant with MM, give the degree that reaction that described compositions causes reaches, the seriousness that partly depends on disease, for example I phase, II phase or III phase, and partly depend on the patient be new diagnosis or suffer from intractable MM in late period.Therefore, in certain embodiments, described pharmaceutical composition cause complete reaction.
In other embodiments, described pharmaceutical composition causes extraordinary partial reaction or partial reaction.
In other embodiments, described pharmaceutical composition causes minimal reaction.
In other embodiments, described pharmaceutical composition stop disease progression, cause being categorized as by EBMT the reaction of " unchanged " or " plateau ".
The route of administration and the dosage range that are used for the treatment of the compositions that comprises anti--CS1 antibody such as HuLuc63 and one or more therapeutic agents of the individuality that is diagnosed as MM, can use the standard technique of this area, such as standard dose increase progressively research measure MTD determine (referring to, Richardson for example, Deng the people, 2002, Blood, 100 (9): 3063-3067, its content is incorporated this paper into by reference).
Typically, anti--CS1 antibody intravenous administration.The administration of described other therapeutic agent herein can be by any mode known in the art.That these modes comprise is oral, rectum, nasal cavity, part (comprising oral cavity and Sublingual) or parenteral (comprising subcutaneous, intramuscular, intravenous and intradermal) administration and partly depend on obtainable pharmaceutical dosage form.For example, can pill or the therapeutic agent that obtains of capsule form oral giving typically.Yet oral administration need to be compared the higher dosage of dosage of intravenous administration usually.Determine that actual route of administration best under concrete condition is in those skilled in the art's limit of power, and partly depend on the comparison of the dosage of needs and the number of times that needs per month to give.
The factor that impact is used in resisting in compositions as herein described and the method-CS1 antibody and therapeutic agent selective dose comprises, but be not limited to this, the type of medicament, the patient's of acceptance age, body weight and clinical symptoms, and the clinician who treats or medical practitioner's experience and judgement.Usually, the dosage of selection should be enough to cause unchanged, but preferably causes at least minimum change.The medicament of effective dose provides objectively identifiable reaction, for example, plateau, unchanged, minimal reaction, partial reaction or complete reaction as being assert by the titular observers of clinician and other, and as are defined by EBMT.
Usually, anti--CS1 antibody, as with respect to the compositions that comprises therapeutic agent independently compositions give.As discussed above, therapeutic agent can be respectively as compositions independently, or be combined in and give in the intermixture and give as the single compositions that is combined.In certain embodiments, comprising the compositions of anti--CS1 antibody and one or more therapeutic agents gives simultaneously.In other embodiments, anti--CS1 antibody can give before comprising the compositions of therapeutic agent.In the embodiment that also has other, anti--CS1 antibody gives after comprising the compositions of therapeutic agent.
Before or after giving therapeutic agent, resist-those embodiments of CS1 antibody in, determine to resist-CS1 antibody and the interval that gives between the described medicament are in those skilled in the art's limit of power, and partly depend on the comparison of dosage with the administration number of times that needs per month of needs.
Be used for as herein described anti--dosage of CS1 antibody typically scope between 0.5mg/kg to 20mg/kg.The optimal dose of therapeutic agent is common received effective dose, such as at the Physician Desk Reference, and the 56th edition (2002) Publisher MedicalEconomics, those described in the New Jersey.The optimal dose of the medicament of in Physician DeskReference, not describing can the Application standard dose escalation study measure MTD determine (referring to, for example Richardson waits the people, 2002, Blood, 100 (9): 3063-3067, its content is incorporated this paper into by reference).
In certain embodiments, anti--CS1 antibody in pharmaceutical composition with concentration, or with weight/volume percent or with weight, be suitable for close rate at least about 0.5mg/kg, at least about 0.75mg/kg, at least about 1mg/kg, at least about 2mg/kg, at least about 2.5mg/kg, at least about 3mg/kg, at least about 4mg/kg, at least about 5mg/kg, at least about 6mg/kg, at least about 7mg/kg, at least about 8mg/kg, at least about 9mg/kg, at least about 10mg/kg, at least about 11mg/kg, at least about 12mg/kg, at least about 13mg/kg, at least about 14mg/kg, at least about 15mg/kg, at least about 16mg/kg, at least about 17mg/kg, at least about 18mg/kg, at least about 19mg/kg, and provide at least about the 20mg/kg intravenous administration.
6. embodiment
Embodiment 1:HuLuc63 and dexamethasone associating
Dexamethasone (Dex) is for being widely used in the corticosteroid for the treatment of MM in multi-thread therapy.Dex unites as single medication or with various medicaments, described medicament comprises lenalidomide, Thalidomide, Bortezomib (velcade) or as VAD (vincristine, doxorubicin, dexamethasone) part of scheme or DVd liposome doxorubicin, vincristine is filled in the Mi Songfang case in short time.The mechanism of action of Dex relates to by the apoptosis of the direct inducing tumor cell of activation of cysteine proteinase (caspases) (people such as Chauhan, 1997, Oncogene 15:837-843; The people such as Chauhan, 1997, J.Biol.Chem.272,29995-29997; The people such as Chauhan, 2001, J.Biol.Chem., 276:24453-24456).
HuLuc63 and Dex treatment to CS1 in MM cell line and the effect of the expression in the mice xenotransplantation tumor respectively by flow cytometry and immunohistochemical detection.
Xenotransplantation mouse model in the body: method and result
Will available from Taconic Farms (Germantown, NY) six thoughtful eight the week ages female IcrTac:ICR-Prkdcscid mice 1x10 7OPM2 or L363 cell (GermanCollection of Microorganisms and Cell Cultures, Braunschweig, Germany) cell is seeded in the bottom right side of body.Implementing weekly twice kind of calliper uses following formula to calculate gross tumor volume: LxWxH/2, wherein L (length) is the longest side of tumor in the plane of back part of animal, and W (width) is vertical with length and the longest dimension in identical plane and H (highly) are measured at the peak perpendicular to back part of animal.If tumor reaches about 100mm 3Mean size, animal is divided into 3 groups of every group of 8-10 mices at random and with 1 or the processing of 10mg/kg HuLuc63 or homotype control antibodies, weekly twice altogether 6 doses of intraperitoneal give.
With the dosage of 10mg/kg weekly twice altogether maximum 6 doses of intraperitoneal give Dex.
1-2 month time of monitoring tumor growth.Animal operates under the guidance of NIH guide (" Guide forthe Care and Use of Laboratory Animals ") uses the experimental program by the IACUC approval to carry out at PDL BioPharma.
The OPM2 multiple myeloma cell line is checked the CS1 protein expression.Do not observing significant change with HuLuc63, Dex or before with these two kinds of chemicals treatment or after processing aspect the CS1 expression.The activity of the associating anti-myeloma in vivo of test HuLuc63 and Dex.HuLuc63 (1mg/kg) or homotype control antibodies weekly twice processing three weeks of the mice of OPM2 tumor with inferior Optimal content will be suffered from.Dex is accepted weekly the mice of homotype control antibodies or HuLuc63 for twice with 10mg/kg.The result show alone HuLuc63 and with the remarkable anti-tumor activity of Dex associating (referring to, Fig. 1 for example).Compare in the single medication group of HuLuc63, the mice in the therapeutic alliance group has shown significantly less tumor (referring to, Fig. 1 for example).
Embodiment 2:HuLuc63 and Thalidomide associating
Thalidomide (Thal) is that approval is united the immunoregulation medicament that is used for the treatment of MM with Dex at present.The mechanism of action of Thal is not understood fully, but relating to angiogenesis suppresses, stromal cell in bone marrow and the growth of tumor cell and survival suppress, and change the generation (such as IL-6, IL-10, IL-4, IL-5, IL-12, IL-8, TNF-α) of the factor that affects myeloma cell's survival.
HuLuc63 and Thal treatment to the effect of the expression of CS1 in MM cell line and mice xenotransplantation tumor respectively by flow cytometry and immunohistochemical detection, as mentioned above.
The L363 multiple myeloma cell line is checked the CS1 protein expression.Do not observing significant change with HuLuc63, Thal or before with these two kinds of chemicals treatment or after processing aspect the CS1 expression.The activity of the associating anti-myeloma in vivo of test HuLuc63 and Thal.With the mice that suffers from the L363 tumor with HuLuc63 or homotype control antibodies with 10mg/kg three weeks of twice processing weekly.With Thal weekly 5 days with the maximum 15 doses of mices of accepting homotype control antibodies or HuLuc63 of 50mg/kg.The joint observation of alone HuLuc63, alone Thal and HuLuc63 and Thal has arrived significant anti-tumor activity (referring to, Fig. 2 for example).Compare the single medication group of HuLuc63 and Thal, the mice in the therapeutic alliance group has shown significantly less tumor (referring to, Fig. 2 for example).
Embodiment 3:HuLuc63 and Thalidomide/dexamethasone associating
The Thal/Dex conjoint therapy is approved for MM patient's first-line treatment at present.Test as described above the interior anti-myeloma activity of body of the associating of HuLuc63 and Thal/Dex.Thal/Dex treatment to CS1 the expression in MM cell line and mice xenotransplantation tumor pass through as mentioned above immunohistochemical detection.
With the mice that suffers from the L363 tumor with HuLuc63 or homotype control antibodies with 10mg/kg three weeks of twice processing weekly.With Thal weekly 5 days with 50mg/kg maximum 15 doses give and with Dex weekly twice with the maximum 6 doses of mices of accepting homotype control antibodies or HuLuc63 of 10mg/kg.The result shows the remarkable anti-tumor activity (referring to, Fig. 3 for example) of the associating of alone HuLuc63, alone Thal/Dex and HuLuc63 and Thal/Dex.Compare the single medication of HuLuc63 or Thal/Dex therapy, the mice in the therapeutic alliance group of HuLuc63/Thal/Dex has shown minimum tumor, dwindles average 50-70% (referring to, Fig. 3 for example) aspect tumor size.
Embodiment 4:HuLuc63 and bevacizumab associating
Bevacizumab is the monoclonal antibody of targeting endothelial cell growth factor (ECGF) VEGF.It works by suppressing VEGF, causes the inhibition of neovascularization in the tumor.Bevacizumab is approved for the treatment solid tumor at present, comprises metastatic colorectal carcinoma.Bevacizumab not yet is approved for treatment MM at present.
Whether can improve the antitumous effect of HuLuc63 in order to measure anti-angiogenic medicaments, as previously discussed, anti-myeloma is active in the body of the associating of test HuLuc63 and bevacizumab.With the mice that suffers from the L363 tumor with HuLuc63 or homotype control antibodies with 10mg/kg three weeks of twice processing weekly.With bevacizumab weekly twice with the maximum 6 doses of mices of accepting homotype control antibodies or HuLuc63 of 0.5mg/kg.Observe alone HuLuc63 and with the remarkable anti-tumor activity of the associating of bevacizumab (referring to, Fig. 4 for example).Alone bevacizumab does not show significant anti-tumor activity.Yet, compare the single medication group of HuLuc63, the mice of accepting the associating of HuLuc63 and bevacizumab has significantly shown less tumor, illustrates that HuLuc63 and bevacizumab can synergism and cause the anti-myeloma effect.
Embodiment 5: be diagnosed as the treatment of multiple myeloma patients
The patient HuLuc63 that suffers from multiple myeloma after the multicenter, opening of bid (open-label), multiple dose, dose escalation study of suggestion will be used for estimating for the first time, recur for the second time or for the third time and a kind of associating of and multiple therapeutic agent.HuLuc63 by intravenous injection (IV) with scope from 2.5mg/kg's to 20mg/kg until 5 dosage levels and one or more therapeutic agents are united gives.The patient accepts HuLuc63, every dose of infusion 1 hour, and weekly, per 10 days are once or whenever biweekly, minimum 4 doses and maximum 52 doses.
Be suitable for medication combined comprising of giving with HuLuc63, but be not limited to:
1) melphalan+prednisone.Melphalan gave with 28 days cycle, at 1 to 4 day with 8mg/m 2/ d, maximum 11 cycles.Prednisone gave with 28 days cycle, at 1 to 4 day 60mg/m 2/ d, maximum 11 cycles;
2) melphalan+prednisone+Thalidomide.With 28 days cycle, at 1 to 4 day with 8mg/m 2/ d gives melphalan, maximum 11 cycles.With 28 days cycle, at 1 to 4 day with 60mg/m 2/ d gives prednisone, maximum 11 cycles.With 28 days cycle, gave Thalidomide at 1 to 4 day with 200mg/d, maximum 11 cycles;
3) melphalan+prednisone+lenalidomide.With 28 days to 42 days cycle, 0.18 to 0.25mg/kg per 4 to 6 weeks to give 4 days melphalans, maximum 9 cycles.With 28 days to 42 days cycle, per 4 to 6 weeks of 2mg/kg to give 4 days prednisones, maximum 9 cycles.With 28 days to 42 days cycle, 5 to 10mg/d per 4 to 6 the 1st to 21 day weeks to give lenalidomide, maximum 9 cycles;
4) melphalan+prednisone+bortezomib.With 42 days cycle, at 1 to 4 day with 9mg/m 2/ d gives melphalan, maximum 4 cycles.With 42 days cycle, at 1 to 4 day with 60mg/m 2/ d gives prednisone, maximum 4 cycles.With 42 days cycle, on the 1st, 4,8,11,22,25,29 and 32 with 1.3mg/m 2/ d gives bortezomib, maximum 4 cycles;
5) Thalidomide+dexamethasone.Cycle with 28 days gives Thalidomide with 200mg/d, maximum 4 to 12 cycles.With 40mg/d on the 1st to 4,9 to 12 days, and gave dexamethasone on the 17th to 20, maximum 4 to 12 cycles;
6) cyclophosphamide (Cytoxan)+prednisone.With 28 days cycle, give once in a week cyclophosphamide with 500mg, maximum 6 cycles.With 28 days cycle, give every other day prednisone with 100mg/d, maximum 6 cycles;
7) cyclophosphamide+prednisone+Thalidomide.With 28 days cycle, give 21 days cyclophosphamide with the every twice-daily of 50mg, maximum 7 cycles.With 28 days cycle, with 100mg/d, give every other day prednisone, maximum 7 cycles.With 28 days cycle, with 200mg/d, give every other day Thalidomide, maximum 7 cycles;
8) cyclophosphamide+prednisone+lenalidomide.With 28 days cycle, gave cyclophosphamide, maximum 4 to 7 cycles on the 1st and the 8th with 300 to 700mg.With 28 days cycle, give every other day prednisone with 50mg/d, maximum 4 to 7 cycles; With 28 days cycle, gave lenalidomide maximum 4 to 7 cycles on the 1st to 21 with 25mg/d;
9) cyclophosphamide+dexamethasone+lenalidomide.With 28 days cycle, gave cyclophosphamide, maximum 4 to 7 cycles on the 1st and the 8th with 300 to 700mg.With 28 days cycle, on the 1st to 4, gave dexamethasone in 9 to 12 days and 17 to 20 with 40mg, maximum 4 to 7 cycles.With 28 days cycle, on the 1st to 21, give lenalidomide with 25mg/d, maximum 4 to 7 cycles;
10) cyclophosphamide+prednisone+bortezomib.With 28 days cycle, gave cyclophosphamide on the 1st, 8,15 and 22 with 300mg, maximum 4 to 7 cycles.With 28 days cycle, give every other day prednisone with 100mg, maximum 4 to 7 cycles.With 28 days cycle, with 1.5mg/m 2/ d gave dexamethasone on the 1st, 8 and 15, maximum 4 to 7 cycles;
11) bevacizumab.With 14 days cycle, with 5mg/kg, per two weeks gave bevacizumab, maximum 6 to 26 cycles;
12) KOS-953+bortezomib.With 21 days cycle, 100 to 340mg/m 2Give weekly two all KOS-953s for twice, maximum 4 to 8 cycles.With 21 days cycle, with 0.7 to 1.3mg/m 2Give weekly two all bortezomibs for twice, maximum 4 to 8 cycles;
13) Doxil (Doxil)+bortezomib.With 21 days cycle, with 30mg/m 2/ d gave Doxil on 4th, maximum 4 to 8 cycles.With 21 days cycle, with 1.3mg/m 2/, at Isosorbide-5-Nitrae, gave bortezomib, maximum 4 to 8 cycles on the 8th to 11; With
14) dexamethasone.With 28 days cycle, with 40mg/d on the 1st to 4,9 to 12 days, and gave dexamethasone on the 17th to 20, maximum 4 to 12 cycles, or alternately, with 28 days cycle, give 4 days with 40mg/d, with 28 days cycle.
Above drug regimen can orally give or give by IV.
After week, assess the EBMT standard at treatment 8-12.If patient disease development is then according to stop using HuLuc63 and cancel or continue to use the other drug combination of field study personnel's judgement.If the patient responded or stable disease in 8-12 week, continue to give the HuLuc63 drug regimen in order to finish the treatment in maximum 52 weeks or to disease progression occurring.
Register about 15 to 30 patients for various drug regimens 5 dosage groups.Each dosage group is from 3 patients.If within initial 4 weeks for the treatment of, in any patient, all do not find dose-limiting toxicity (DLT), begin to register next higher dosage group, if DLT appears in a patient, this dosage group will be registered 3 extra patients.If in this dosage group, the patient of DLT occurs without other, can continue to be increased to next dosage group.If DLT appears in second patient in the dosage group, then reach maximum tolerated dose (MTD).
Dose-limiting toxicity (DLT) uses national Cancer center institute common toxicity standard 3.0 editions (NCI CTCAE v3.0) to be defined as 4 grades of haematics toxicities or hyperbilirubinemia, or 3 grades of toxicity is in being considered as any other system relevant with the associating of any medicine of enumerating in HuLuc63 or HuLuc63 and the table 1.To next dosage group, three appreciable patients must finish the dosage in their initial 4 weeks for dosage escalation.If there is DLT, then increase by three extra appreciable patients.By the adverse events of assessment by NCI CTCAE v3.0 classification the patient is carried out Safety monitoring and uses EBMT to the patient monitoring Clinical efficacy.Maximum tolerated dose (MTD) is defined as the maximum dose level of the incidence rate of the DLTs of research＜33%.If do not observe dose-limiting toxicity, maximum tolerated dose is the associating of the medicine of 20mg/kg HuLuc63 and the above dosage of enumerating.
All publications of quoting among the application, patent, patent application and other file are autotelic all by with reference to incorporating the application into for the institute of same range as, as with each publication, patent, patent application or other file for all purposes separately explanation.
Illustrate and described different specific embodiments, in situation without departing from the spirit and scope of the present invention, can implement different variations.

Claims (12)

1. the combination product that is used for the treatment of multiple myeloma, it comprises simultaneously, separately or HuLuc63 and one or both therapeutic agents of sequential application, and wherein said one or both therapeutic agents are dexamethasone or dexamethasone and Thalidomide.
2. according to claim 1 the combination product that is used for the treatment of multiple myeloma is wherein used HuLuc63 with the dosage intravenous of 0.5mg/kg to 20mg/kg.
3. according to claim 1 and 2 the combination product that is used for the treatment of multiple myeloma, wherein said HuLuc63 and one or both therapeutic agents cause complete reaction, and wherein said complete reaction is defined as minimum 6 weeks not detect M albumen and detect in bone marrow in serum or urine by immunofixation and is less than 5% plasma cell.
4. according to claim 1 and 2 the combination product that is used for the treatment of multiple myeloma, wherein said HuLuc63 and one or both therapeutic agents cause M albumen and reduce and surpass 90%.
5. according to claim 1 and 2 the combination product that is used for the treatment of multiple myeloma, wherein said HuLuc63 and one or both therapeutic agents cause in the serum M protein level reduce＞50% and/or urine in free light chain secretion reduce by 90% or be reduced to＜200mg/24 hour, continued for 6 weeks.
6. according to claim 1 and 2 the combination product that is used for the treatment of multiple myeloma, the M protein level reduces free light chain secretion reduction 50-89% in 25-49% and/or the urine in wherein said HuLuc63 and one or both therapeutic agents initiation serum, still surpass 200mg/24 hour, continued for 6 weeks.
7.HuLuc63 with one or both therapeutic agents for the preparation of the treatment multiple myeloma medicine in purposes, wherein said one or both therapeutic agents are dexamethasone or dexamethasone and Thalidomide.
8. according to claim 7 purposes is wherein used HuLuc63 with the dosage intravenous of 0.5mg/kg to 20mg/kg.
9. according to claim 7 or 8 purposes, wherein said HuLuc63 and one or both therapeutic agents cause complete reaction, and wherein said complete reaction is defined as minimum 6 weeks not detect M albumen and detect in bone marrow in serum or urine by immunofixation and is less than 5% plasma cell.
10. according to claim 7 or 8 purposes, wherein said HuLuc63 and one or both therapeutic agents cause M albumen and reduce and surpass 90%.
11. according to claim 7 or 8 purposes, wherein said HuLuc63 and one or both therapeutic agents cause in the serum M protein level reduce＞50% and/or urine in free light chain secretion reduce by 90% or be reduced to＜200mg/24 hour, continued for 6 weeks.
12. according to claim 7 or 8 purposes, wherein said HuLuc63 and one or both therapeutic agents cause in the serum M protein level and reduce that free light chain secretion reduces 50-89% in 25-49% and/or the urine, still surpass 200mg/24 hour, continue for 6 weeks.
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