CN108026123A - Hydrophilic chain junctor for coupling - Google Patents
Hydrophilic chain junctor for coupling Download PDFInfo
- Publication number
- CN108026123A CN108026123A CN201580080839.3A CN201580080839A CN108026123A CN 108026123 A CN108026123 A CN 108026123A CN 201580080839 A CN201580080839 A CN 201580080839A CN 108026123 A CN108026123 A CN 108026123A
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- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
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- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
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Abstract
Present patent application provides the cell-binding molecules drug conjugates for including hydrophilic chain junctor, and the method using these chain junctors and conjugate.
Description
Technical field
The present invention relates to for medicine, particularly cytotoxic agent or chromophore molecule to be coupled to cell-binding molecules
The preparation of hydrophily chain junctor.The invention further relates to prepare (the coupling of cell binding agent-medicine (such as cytotoxic agent) conjugated body
Thing) method, it includes first modifying medicine with these hydrophilic linkers, then with cell binding agent react;Or
First with these hydrophily connexon modified cells bonding agents, then and drug response.
Background technology
The treatment of targeting is always the emphasis of medical research and development for many years, is the foundation stone (Ba La of " accurate medicine "
Gram president Obama, the State of the Union Message, on January 20th, 2015, www.whitehouse.gov/precisionmedicine).
It is come assisted diagnosis using the customizing messages of human tumor, and how planned treatment, find therapeutic effect, or makes prediction
(FS Collins, New Engl.J.Med.2015;372:793-795).So far, food officina of the U.S. (FDA), European medicine
Prison committee (EMA) and food officina of China (CFDA) have approved many different targeted therapies and be used for treatment of cancer.These therapies
Including hormonotherapy, signal transduction inhibitor, gene expression regulator, inducer of apoptosis, angiogenesis inhibitors, immunotherapy
With toxin delivery molecule.Hormonotherapy by preventing body from producing hormone or work by disturbing functions of hormones, its after
And the growth of hormone-sensitive tumour can be slowed or shut off.Signal transduction inhibitor blocks letter of the cellular response from its environment
Number, particularly prevent cancer cell from breeding rapidly and invade the ability of its hetero-organization.Gene expression regulator, which can be modified, to be controlled
The function of the protein to work in gene expression.Cell death inducer cause cancer cell be subjected to control cell death mistake
Journey.Angiogenesis inhibitors block growth (process that is known as Tumor Angiongesis) of the new blood vessel to tumour.Immunotherapy triggers
Immune system destruction cancer cell.Most of immunotherapy is to identify the monoclonal antibody of cancer cell surfaces specific molecular.Toxin
Toxin pharmaceutical specificity is delivered to cancer cell by delivery molecule using carrier/method.
Over the past thirty years come widely studied comparison gather effect method be toxin delivery molecule.There are several systemic deliveries
Chemotherapeutics is used for the targeted therapy of tumour:Hot activation targeted delivery of drugs;Using carrier mediated transportation system to cancer into
The selective medicine delivery of row tissue;The prodrug therapy that tumour for targeted delivery chemotherapy activates;Medicine is lured across vascular pressure
Lead and be filled into tumour;Cancer therapy drug selectively penetrating is promoted to enter tumour;Targeted using two steps of bispecific antibody;Antibody coupling
The delivering of the specific position of thing;With the photoactivation method of macromolecular.Many carriers are matched somebody with somebody in different forms or with special
Side is used for the research of targeted delivery cancer therapy drug, such as albumin based medicine carrier;Carbohydrate enhancement chemotherapy;Based on albumen
The pharmaceutical carrier of matter and peptide;Aliphatic acid as the targeting vector being connected with active medicine;It is microsphere supported;Monoclonal antibody conduct
Carrier;Vitamin, such as folic acid is as carrier;Nanoparticle vector;Liposome vectors, such as pegylated liposomal (encapsulating
In polyethylene glycol bilayer);Polyethylene glycol (PEG) carrier;Single chain antigen binding molecule carrier;Polymer micelle carrier;It is based on
The pharmaceutical carrier of lipoprotein;Dendrimer;Etc..Preferable delivery vector must be locus specificity, nontoxic, biological degree phase
Hold, non-immunogenic and organism degradable (Scott, R.Et al., (2008) Expert Opin.Drug Deli.5,
459) and avoid identifying (Saltzman, W. (2008) " Drug delivery systems " by the defense mechanism of host
Access Science.McGraw-Hill Co.).By this standard, the defeated of chemotherapeutics is used as using monoclonal antibody (mAb)
It is then successful to send carrier.By the way that unique targeting ability of monoclonal antibody and the cancer ability of killing of cytotoxic drug are mutually tied
Close, antibody-drug conjugates (ADC) can sensitively distinguish health and diseased tissue (ADC Review, J.Antibody-drug
Conjugates ,-Jun 1,2013).Except 2013 ado-trastuzumab emtansine were successfully listed in U.S. FDA
(T-DM) and outside the Brentuximab vedotin by U.S. FDA in 2011, had more than at present in U.S. clinical trial
40 kinds of different ADC medicines (www.clinicaltrials.gov).But the development of ADC also has many challenges, for example control
The improved chain junctor selection of index is treated, the monoclonal antibody (mAb) of link is to target selection, the understanding to mechanism of action, and inclined to ADC
The management for the toxicity moved target and produced and understanding problem.The connector being currently known between delivery vehicles, especially antibody and
Connector between cell killing toxin plays a crucial role in the development of targeted drug delivery system, because the property of attachment is shown
Landing influences the activity of conjugate, selective and pharmacokinetics (Zhao, R.Y. et al. (2011) J.Med.Chem.54,
3606;Acchionea, M. et al. (2012) mAbs, 4,362;Doronina, S. et al., (2006) Bioconjug.Chem,
17,114;Hamann, P. et al. (2005) Bioconjug.Chem.16,346).Up to the present, there is the link of four types
Body is commonly used for preparing into clinical cell-binding molecules-drug conjugates:(a) the unstable chain junctor of acid, it utilizes acidity
Inner body and the intracellular microenvironment of lysosome;(b) can be by the chain junctor of lysosomal protein cleavage;(c) chemically stable thioether chain
Junctor, discharges lysyl adduct after its antibody protein hydrolytic degradation in the cell;Exposed into the cell can by sulphur (d)
The chain junctor (Zhao, R.Y. et al., 2011J.Med.Chem.36,5404) containing disulfide bond of alcohol cracking.
Via the cell binding agent of different types of connector and the conjugate of medicine or cell binding agent and the change of modification
The conjugate of chemical combination thing have been reported (U.S.Patent Nos.4,680,338,5,122,368,5,141,648,5,208,
020,5,416,064;5,475,092,5,543,390,5,563,250 5,585,499,5,880,270,6,214,345,6,
436,931,6,372,738,6,340,701,6,989,452,7,129,261,7,375,078,7,498,302,7,507,
420,7,691,962,7,910,594,7,968,586,7,989,434,7,994,135,7,999,083,8,153,768,8,
236,319,WO2014080251,Zhao,R.;et al,(2011)J.Med.Chem.36,5404;Doronina,S.;et
al,(2006)Bioconjug Chem,17,114;Hamann,P.;et al.(2005)Bioconjug Chem.16,346).
In general, in these conjugates, first with bifunctional reagent such as SPDP (N- succinimidos 3- (2- pyridyidithios)
Propionic ester), SMPDP (N- succinimido 4- methyl -4- (2- pyridyidithios)) valerate), (4- succinyls are sub- by SPDB
Amido 4- (2- pyridine radicals two is thio) butyrate) or SMCC (succinimido -4- (N- maleimidomehyls) hexamethylene -
1- carboxylates) to introduce reactive disulfides or maleimid moiety.Reaction with the cytotoxic drug containing sulfydryl obtains
Pass through disulfide bond or the conjugate of thioether key connection between cell binding agent such as monoclonal antibody and medicine.
However, it is used for using cell-binding molecules-drug conjugates (such as antibody-drug conjugates (ADC)) exploitation each
The therapy of kind cancer has been limited to the availability of specific targeting agent (carrier) and the content when the medicine on conjugate carrier
The coupling method for causing protein aggregate to be formed during (that is, drug loading) increase.Carried out in general, working as with hydrophobic connexon
During coupling reaction, the trend of cytotoxic drug conjugate aggregation is particularly problematic.Since higher drugloading rate adds coupling
The intrinsic effect of thing, can be consistent with the affinity of body protein published originally it is desirable that carrying sufficient dose carrier.The protein of aggregation, it can
It can be non-specific toxicity and immunogenicity, it is therefore necessary to removed in treatment use so that large-scale production conjugate
During yield that is more difficult and reducing product.
We had once invented a series of containing phosphinic acids root, and the hydrophily chain junctor of sulfonyl and/or sulfoxide radicals, it can
Cytotoxic drug be coupled to carrier (cell-binding molecules) under high drug load and occur without the side of aggregation for improving
Method (PCT/IB2012/056700and PCT/CN2014/072769).Herein, we continue description hydrophilic chain junctor, can be with
Preferably be coupled, the insoluble drug release of having ready conditions property, at the same each chain junctor load two distinct types of medicine or molecule,
And/or the site of each a pair of of cell-binding molecules of chain junctor connection obtains specificity or preferably coupling.
Brief summary of the invention
The present invention provides containing phosphamide, phosphamide, sulfonamide, sulfonyl, the parent of sulfimide and/or sulfoxide radicals
Water-based chain junctor by medicine to be connected to cell binding agent (such as antibody).Cell-binding molecules-hydrophily chain junctor-medicine is even
The optimization formula of connection thing (conjugated body) can be expressed as:Cb-(-L-Drug)n, wherein Cb is cell binding agent, and L is hydrophily chain
Junctor, Drug are drug molecules, and n is 1 to 20 integer.Connected in cell-binding molecules-drug conjugates using hydrophily
The advantages of body is:A) reduces the aggregation of conjugate in aqueous medium;B) can obtain the agent-cell binding molecule with higher
Ratio conjugate, causes the effect of higher;C) medicines-chain junctor can be trapped in target cell after being discharged from conjugate, can be supported
Multidrug resistance (MDR) cell of permeability resistance glycoprotein (Pgp) expression;D) allows each chain junctor to load two kinds of different medicines
Thing;F) site of each a pair of of the cell-binding molecules of chain junctor coupling of.
In one aspect of the invention, hydrophily linker is represented by formula (I):Wherein Y can be reacted with cell binding agent,
Z can be reacted with cytotoxic drug:
Wherein:
Y represents the functional group that can be reacted with cell binding agent;
Q and T is-X1- P (=O) (OM)-, or X1-S(O2)-, or-X1–S(O)-;Or-X1- P (=O) (OM)-X2-, or-
X1- P (=O) [X2-R4-Z]-X3-, or-X1- P (=O) [X2-R1-Y]-X3-, or-X1-S(O2)-X2-, or-X1–S(O)-X2-;
X1,X2And X3Independently selected from N (R7), O, or S;In addition, work as X1It is N (R7), or during O or S, then X2Or X3It is or another
A X1With-P (=O) ,-S (O), or-S (O2) connection when, X2Or X3Or another X1Can be CH2;
M and n is the integer from 0 to 5, but cannot be 0 at the same time;
Z represents a functional group, can be by thio, thioesters, peptide, hydrazone, ether, ester, carbamate, carbonic ester, amine
(two level, three-level or level Four), imines, cycloheteroalkyl, heteroaromatic group, one cytotoxic drug of alkane oxime or acid amides key connection;
R1,R2,R3,R4,R5,R6, and R7It is, it is identical or different, it is H, the straight chained alkyl with 1-6 carbon atom, has 3-
The side chain or cyclic alkyl of 6 carbon atoms, straight chain, side chain or cyclic alkenyl or alkynyl, ester, ether, the acyl of 1-6 carbon atom
Amine, or molecular formula are (OCH2CH2)p, polyethyleneoxy unit, wherein p are the integers of 0 to about 1000, or combinations thereof,
In addition, R1,R2,R3And R4It is the atomic link selected from C, N, O, S, Si and P respectively, it is to be covalently attached cell surface
Binding partner, phosphinates or sulfonyl group, the medicine of coupling and (R between them1,R2, R3And R4) connection.For being formed
The atom of hydrophily chain junctor can combine in a manner of all chemistry are relevant, such as form alkyl, alkene, alkylidene, alkenylene,
Alkynyl, ether, polyoxyalkyl, ester, amine, imines, polyamines, hydrazine, hydrazone, acid amides, urea, semicarbazides, carbonohydrazides, alkoxyamine, amino
Formic acid esters, amino acid, peptide, acyloxy amine, hydroxamic acid or its combinations of the above.
M is H, or Na, or K, or N+R1R2R3Or pharmaceutical salts.Above to R1,R2And R3It is described.
In another embodiment, when the hydrophily chain junctor of formula (I) has two or more Y groups, particularly
During two identical Y groups, in this case, Q or/and T are-- X1- P (=O) [X2-R1-Y]-X3-, then the parent of formula (I)
Water-based chain junctor can connect two or more sites, be especially connected to a loci of cell-binding molecules.
In another embodiment, when the hydrophily chain junctor of formula (I) has two or more Z groups, at this
In the case of kind, Q or/and T are-X1- P (=O) [X2-R4-Z]-X3-, then the hydrophily chain junctor of formula (I) may be connected to two kinds
Or more kind medicine, particularly two kinds of different medicines.
On the other hand, the present invention provides the Cell binding agent-drug conjugates titer of formula (II), wherein cell binding agent Cb and
Medicine, Drug, links at the both ends of hydrophily chain junctor:
Wherein:
Cb represents cell binding agent;
Drug is represented with disulphide, thioether, thioesters, peptide, hydrazone, ether, ester, carbamate, carbonic ester, cycloheteroalkyl,
Medicine heteroaromatic, that alkoxy or amido link are connected by hydrophily chain junctor with cell binding agent;
Q is 1~20;m,n,R1,R2,R3,R4,R5,R6It is identical with the description in foregoing formula (I) with M;
Q and T is-X1- P (=O) (OM)-, or-X1-S(O2)-, or-X1–S(O)-;Or-X1- P (=O) (OM)-X2-, or-
X1- P (=O) [X2-R4-Drug]-X3-, or-X1- P (=O) [X2-R1-Cb]-X3-, or-X1-S(O2)-X2-, or-X1–S(O)-
X2-;
X1,X2And X3Independently selected from N (R7), O, or S;In addition, work as X1It is N (R7), or during O or S, then X2Or X3It is or another
A X1With-P (=O) ,-S (O), or-S (O2) connection when, X2Or X3Or another X1Can be CH2;
On the other hand, the present invention provides formula (III) modification cell binding agent, wherein cell binding agent Cb with
Still the hydrophily chain junctor with Z reacts, which has the ability that can be reacted with medicine:
Wherein Cb, Z, m, n, q, R1,R2,R3,R4,R5And R6It is identical with the definition in formula (I) and (II).
Q and T is-X1- P (=O) (OM)-, or-X1-S(O2)-, or-X1–S(O)-;Or-X1- P (=O) (OM)-X2-, or-
X1- P (=O) [X2-R4-Z]-X3-, or-X1- P (=O) [X2-R1-Cb]-X3-, or-X1-S(O2)-X2-,or–X1–S(O)-X2-;
X1,X2And X3Independently selected from N (R7), O, or S;In addition, work as X1It is N (R7), or during O or S, then be connected to-P (=
), O-S (O), or-S (O2) X2, or X3, or another X1, can be CH2。
Another further aspect, the present invention provides the modified medicine of formula (IV), wherein medicine, Drug, with still having Y
Hydrophily reactive group, which can react with cell-binding molecules:
Wherein Y, Drug, m, n, q, R1,R2,R3,R4,R5And R6It is identical with the definition in formula (I) and (II);
Q and T is-X1- P (=O) (OM)-, or-X1-S(O2)-, or-X1–S(O)-;Or-X1- P (=O) (OM)-X2-, or-
X1- P (=O) [X2-R4-Drug]-X3-, or-X1- P (=O) [X2-R1-Y]-X3-, or-X1-S(O2)-X2-, or-X1–S(O)-
X2-;
X1,X2And X3Independently selected from N (R7), O, or S;In addition, work as X1It is N (R7), or during O or S, then be connected to-P (=
), O-S (O), or-S (O2) X2, or X3Or another X1, can be CH2。
The invention further relates to the method for the cell-binding molecules-drug conjugates for preparing formula (II), wherein medicine leads to
Hydrophily chain junctor is crossed to be connected with cell binding agent.
The invention further relates to prepare formula (III) modification cell-binding molecules method, wherein cell-binding molecules with
Hydrophily chain junctor reacts.
The invention further relates to the method for the modification of pharmaceutical for preparing formula (IV), wherein medicine is reacted with hydrophilic linkers.
Brief description of the drawings
Fig. 1 show the phosphamide chain junctor containing maleimide base group synthesis and these chain junctors antibody with
Application in drug coupling.
Fig. 2 show the phosphamide chain junctor containing disulfide bond synthesis and these chain junctors in antibody and drug coupling
In application.
Fig. 3 show the phosphamide chain junctor containing maleimide base group synthesis and these chain junctors antibody with
Application in drug coupling.
Fig. 4 shown containing maleimide, the synthesis of the phosphamide chain junctor of hydrazone or sulfide group and these links
Application of the body in antibody and drug coupling.
Fig. 5 shows that the synthesis of the steric hindrance type phosphamide chain junctor containing maleimide base group and these chain junctors exist
Antibody and the application in drug coupling.
Fig. 6 show containing disulphide or oximido group phosphamide chain junctor synthesis and these chain junctors in antibody
With the application in drug coupling.
Fig. 7 shows the synthesis and these links of the phosphamide chain junctor containing maleimide and polyethylene group
Application of the body in antibody and drug coupling.
Fig. 8 shown containing maleimide, the synthesis of the phosphamide chain junctor of polyethylene glycol and azido group and this
A little applications of the chain junctor in the coupling of antibody compound different from two kinds.Drug1And Drug2Can be for treatment use
Cytotoxic agent or the chromophoric group compound of the interaction for monitoring conjugate and target cell.
Fig. 9 shown containing disulphide, the synthesis of the phosphamide chain junctor of polyethylene glycol or ketone groups, and these are linked
Body is used to make protein compound coupling different from two kinds.Drug1And Drug2It can be the cytotoxic agent for treatment use
Or for monitoring the chromophore compound of conjugate and neuron target cell interaction.
Figure 10 shows synthesis and these companies of the sulfonamide comprising maleimide base group and sulfenamide connexon
Connect application of the son in the coupling of antibody and cytotoxic drug.
Figure 11 shown containing disulphide, the synthesis of the sulfonamide chain junctor of polyethylene glycol or ketone groups, and chain junctor
For making protein compound coupling different from two kinds.Drug1And Drug2Can be for treatment use cytotoxic agent or
For monitoring the chromophore compound of conjugate and neuron target cell interaction.
Figure 12 shows the synthesis of the phosphamide chain junctor containing thioether or disulphide group, and these chain junctors are used
In two kinds of medicine/compounds for connecting each chain junctor.Here medicine can be for treatment use cytotoxic agent or
For monitoring the chromophore compound of conjugate and neuron target cell interaction.
Figure 13 is shown by the phosphamide chain junctor synthetic antibody conjugate containing Liang Ge functional groups, one of group
Be connected to cytotoxic agent MMAF be used for orient kill, fluorescent dye groups of another connection are for monitor conjugate thin with target
The interaction of born of the same parents.
Figure 14 shows the synthesis of the phosphamide chain junctor containing Liang Ge functional groups.
Figure 15 is shown via the phosphamide chain containing tubulin inhibin analog and MMAF analogs on chain junctor
The synthesis of the antibody coupling matter of junctor.
Figure 16 shows the phosphamide link containing two kinds of differential cytotoxicity medicines (PBD dimers and MMAF analogs)
The synthesis of body.
Figure 17 shows the phosphamide chain junctor synthetic antibody conjugate by this patent.Chain junctor can each chain junctor
Two kinds of different medicines (such as PBD analogs and MMAF analogs) are coupled, or may be coupled to the half Guang ammonia of a couple of antibody
On sour site.
Figure 18 shown containing disulphide, polyethylene glycol, the synthesis of the sulfonamide chain junctor of azido or triazole group
This chain junctor is used for the coupling of the compound different from two kinds.
Detailed description of the invention
Definition
" alkyl " refers to the aliphatic hydrocarbon group for having the straight or branched of 1 to 8 carbon atoms in chain." side chain " refers to one
Or alkyl such as methyl, the ethyl or propyl group of multiple relatively low C numbers are connected on a linear alkyl chain.Alkyl embodiment includes first
Base, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, pentane base, 3- pentyls, octyl, nonyl, decyl, ring
Pentyl, cyclohexyl, 2,2- dimethylbutyls, 2,3- dimethylbutyls, 2,2- dimethyl amyl groups 2,3- dimethyl amyl groups, 3,
3- dimethyl amyl groups, 2,3,4- tri-methyl-amyls, 3- methylhexyls, 2,2- dimethylhexanyls, 2,4- dimethylhexanyls, 2,5- bis-
Methylhexyl, 3,5- dimethylhexanyls, 2,4- dimethyl amyl groups, 2- methylheptyls, 3- methylheptyls, n-heptyl, different heptyl, just
Octyl and isooctane base.C1-C8Alkyl can be unsubstituted or following, but be not limited to following one or more
Group substitutes:C1-C8Alkyl, C1-C8Alkoxy, aryl ,-C (O) R' ,-OC (O) R' ,-C (O) OR' ,-C (O) NH2,-C(O)
NHR',-C(O)N(R')2-NHC(O)R',-S(O)2R' ,-S (O) R' ,-OH, halogen (- F ,-Cl ,-Br, or-I) ,-N3,-
NH2,-NH(R'),-N(R')2And-CN;Wherein R ' refers to each independent C1-C8Alkyl or aryl.
Halogen atom refers to fluorine, chlorine, bromine, preferably iodine atom, fluorine and chlorine atom.
" miscellaneous alkyl " refers to C2-C8Alkyl, wherein the hetero atom that one to four carbon atoms are made of O, S and N is independently replaced
Form.
" carbocyclic ring " refers to that a saturation or undersaturated ring have pair of 3 to 8 carbon atoms as a list or 7 to 13 carbon atoms
Ring.Monocyclic carbocyclic ring has 3 to 6 annular atoms, usual 5 or 6 annular atoms.Bicyclic carbocyclic has 7 to 12 annular atoms, forms as bicyclic [4,5],
[5,5], [5,6] or [6,6] system, or 9 or 10 annular atoms composition is bicyclic [5,6] or [6,6] system.Represent C3-C8Carbocyclic ring bag
Include, but be not limited to,-cyclopropyl,-cyclobutyl,-cyclopenta,-cyclohexyl, -1,3- cyclohexadienyls,-Isosorbide-5-Nitrae-cyclohexadienyl, -
Suberyl, -1,3-- cycloheptadiene bases, -1,3,5- cycloheptatriene bases,-cyclooctyl, and-cyclo-octadiene base.
“C3~C8Carbocyclic ring " refers to containing 3-, 4-, 5-, 6-, 7-, or the saturation of 8 carbon atoms or undersaturated non-aromatics ring-type
Compound.C3-C8Carbon ring group includes non-substituted or one or more substituents and includes, but not limited to C1-C8Alkyl, C1-C8Alcoxyl
Base, aryl ,-C (O) R' ,-OC (O) R' ,-C (O) OR' ,-C (O) NH2,-C(O)NHR',-C(O)N(R')2,-NHC(O)R',-
SR',-S(O)R',-S(O)2R' ,-OH, halogen ,-N3,-NH2,-NH(R'),-N(R')2And-CN;Wherein R ' refers to each independent
C1-C8Alkyl or aryl.
" alkenyl " refers to the aliphatic hydrocarbyl containing carbon-to-carbon double bond, it can be the straight chain in chain with 2-8 carbon atom
Or side chain.Alkenyl example includes vinyl, acrylic, n-butene base, isobutenyl, 3- methyl but-2-ene bases, n-pentene
Base, hexenyl, heptenyl, octenyl.
" alkynyl " refers to the aliphatic hydrocarbyl containing carbon-to-carbon triple bond, it can have the straight of 2 to 8 carbon atoms in chain
Chain or side chain.Example alkynyl includes acetenyl, propinyl, positive butynyl, 2- butynyls, 3- methylbutynyls, 5- pentynyls, just
Pentynyl, hexin base, heptynyl and octynyl.
" alkylidene " refers to the side chain with the saturation of 1-18 carbon atom or straight chain or cyclic hydrocarbon group, and with two
By removing two hydrogen atoms from identical or two different carbon atoms of script alkane and derivative univalent perssad alkane.Typical case
Alkylidene include but not limited to:Methylene (- CH2-), 1,2- ethyl (- CH2CH2-), 1,3- propyl group (- CH2CH2CH2-), 1,
4- butyl (- CH2CH2CH2CH2-), etc..
" alkenylene " refers to the undersaturated side chain or straight chain or cyclic hydrocarbon group with 2-18 carbon atom, and with two
It is a by removing two hydrogen atoms from script alkene identical or two different carbon atoms and derivative univalent perssad center alkene
Hydrocarbon.Typical alkenylene includes but not limited to:1,2- ethylidene (- CH=CH-).
" alkynylene " refers to the undersaturated side chain or straight chain or cyclic hydrocarbon group with 2-18 carbon atom, and with two
It is a by removing two hydrogen atoms from script alkynes identical or two different carbon atoms and derivative univalent perssad center alkynes.
Typical alkynylene includes but not limited to:Acetylene, propargyl and 4- pentynyls.
" aryl " or Ar refer to by one or several ring groups into aromatics or heteroaromatic group, it includes three to 14 carbon
Atom, preferably six to ten carbon atoms." heteroaromatic group " refers to one or several carbon on aromatic group, it is preferable that
One, two, three or four carbon atom are preferably substituted by O, S and N by O, N, Si, Se, P or S.The aryl or Ar also refer to
Aromatic group, wherein one or more H atoms are independently by-R' ,-halogen ,-OR ' ,-SR ' ,-NR ' R " ,-N=NR ' ,-N=
R’,-NR’R”,-NO2,-S(O)R’,-S(O)2R’,-S(O)2OR’,-OS(O)2OR’,-PR’R”,-P(O)R’R”,-P(OR’)
(OR ") ,-P (O) (OR ') (OR ") or-OP (O) (OR ') (OR ") substitutions, wherein R ', R " independently are H, alkyl, alkenyl, alkynes
Base, miscellaneous alkyl, aryl, aryl alkyl, carbonyl or pharmaceutical salts.
" heterocycle " refers to a loop system, and 1 to 4 carbon atom is independently of one another by miscellaneous element, such as O, N, S, Se and P in its middle ring
Substituted.It is preferred that miscellaneous element is O, N and S.The explanation of related heterocycles also can be found in The Handbook of Chemistry
and Physics,78thEdition, CRC Press, Inc..1997-1998, p.225 to 226, and the text of book citation
In offering.Preferable nonaromatic heterocycles base includes but not limited to epoxy group, acridinyl, epithio vinyl, pyrrolidinyl, pyrazolidine
Base, imidazolidinyl, Oxyranyle, tetrahydrofuran base, dioxolanyl, THP trtrahydropyranyl, dioxane hexyl, piperidyl,
Piperazinyl, morpholinyl, pyranose, imidazolinyl, pyrrolinyl, pyrazolinyl, thiazolidinyl, tetrahydrochysene sulphur pyranose, dithiane
Base, thiomorpholine base, dihydro pyranyl, THP trtrahydropyranyl, tetrahydro pyridyl, dihydropyridine base, tetrahydro-pyrimidine base, dihydro sulphur pyrans
Base, nitrogen heterocyclic heptyl and the condensed ring that they generate with phenyl.
Term " heteroaryl " or aromatic heterocycle refer to 5 to 14, preferably 5 to 10 unit aromatic heterocycles, monocyclic, bicyclic or more
Ring.Its example includes pyrrole radicals, pyridine radicals, pyrazolyl, thienyl, pyrimidine radicals, pyrazinyl, tetrazole radical, indyl, quinolyl,
Purine radicals, imidazole radicals, thiazolyl, benzothiazolyl, furyl, benzofuran, 1,2,4-- thiadiazolyl group, isothiazolyl, triazole
Base, tetrazole radical, isoquinolyl, pyrazolyl, thiazolyl, benzothienyl, isobenzofuran-base, pyrazolyl, carbazyl, benzo miaow
Oxazolyl, isoxazolyl, pyridinyl-N-oxide, and the chimeric system being condensed to yield with phenyl.
" alkyl ", " cycloalkyl ", " alkenyl ", " alkynyl ", " aryl ", " heteroaryl ", " heterocycle " etc. also refer to corresponding " alkylene
Base ", " cycloalkylidene ", " alkynylene ", " arlydene ", " inferior heteroaryl " " heterocycle alkene " etc. are by removing two hydrogen atoms and shape
Into.
" aryl alkyl " refer in acyclic alkyl with carbon atom (be usually end or sp3Carbon atom) bonding a hydrogen atom
It is substituted with aryl.Typical aralkyl includes but not limited to benzyl, 2- diphenylphosphino ethane -1- bases, 2- phenylethylene -1- bases, naphthyl
Methyl, 2- naphthyl second -1- bases, 2- naphthylethen -1- bases, naphtho--benzyl, beta naphthal base ethane -1- bases etc..
" heteroaryl alkyl " refer in acyclic alkyl with carbon atom (be usually end or sp3Carbon atom) bonding a hydrogen it is former
Son is substituted by heteroaryl.Typical heteroarylalkyl includes but not limited to 2- benzimidazole ylmethyls, 2- furanylethyls etc..
The example of " hydroxyl protection base " includes but not limited to methoxy ether, 2- methoxyethoxymethyl ethers, tetrahydrochysene
Pyranose ether, benzylic ether, to methoxy-benzyl ether, trimethyl silyl ether, triethylsilyl ether, triisopropyl first silicon
Alkyl ether, t-butyldimethylsilyl ether, trityl group silyl ether, acetic acid esters, substituted acetic acid esters, neopentanoic acid
Ester, benzoic ether, methanesulfonates and p-methyl benzenesulfonic acid ester.
" leaving group " refers to the functional group that can be substituted by another functional group.Such leaving group is in ability
Domain is well-known, and the example includes but not limited to halide (such as chloride, bromide and iodide), mesyl
(mesyl), p-toluenesulfonyl (tosyl), trifluoromethyl sulfonyl (trifluoromethanesulfonic acid ester group) and trifluoromethane sulfonic acid ester.
Following abridge and with the definition specified can be used herein:Boc, tert-butoxycarbonyl;BroP, bromo tripyrrole
Wan Ji Phosphonium hexafluorophosphates;CDI, 1,1'- carbonyl dimidazoles;DCC, dicyclohexyl carbodiimide;DCM, dichloromethane;
DIAD, diisopropyl azo-2-carboxylic acid;DIBAL-H, diisobutyl aluminium hydride;DIPEA, diisopropylethylamine;DEPC, diethyl
Phosphinylidyne cyanate;DMA, n,N-dimethylacetamide;DMAP, 4- (N, N- dimethylamino) pyridine;DMF, N, N- dimethyl methyl
Acid amides;DMSO, dimethyl sulfoxide (DMSO);DTT, dithiothreitol (DTT);EDC, 1- (3- dimethylamino-propyls) -3- ethylcarbodiimine salt
Hydrochlorate;ESI-MS, electrospray ionization mass spectrum;HATU, O- (7- azepine benzos triazol-1-yl)-N, N, N', N'- tetramethylurea hexafluoro phosphorus
Hydrochlorate;HOBt, I-hydroxybenzotriazole;HPLC, high pressure liquid chromatography;NHS, n-hydroxysuccinimide;MMP, 4- methyl
Quinoline;PAB, aminobenzyl;PBS, phosphate buffered saline (PBS) (pH7.0~7.5);PEG, polyethylene glycol;SEC, MW exclusion
Chromatography;TCEP, three (2- carboxyethyls) phosphines;TFA, trifluoroacetic acid;THF, tetrahydrofuran;Val, valine.
" pharmaceutically " or " pharmaceutically acceptable " refer to not produce when being suitably applied to animal or people it is unfavorable,
Allergy or other adverse reactions molecular entities and composition.
" pharmaceutically acceptable solvate " or " solvate " refer to one or more solvent molecules and disclosedization
The association of compound.The example for forming the solvent of pharmaceutically acceptable solvate includes but not limited to water, isopropanol, ethanol,
Methanol, DMSO, ethyl acetate, acetic acid and monoethanolamine.
" pharmaceutically acceptable excipient " includes any carrier, diluent, adjuvant or excipient, such as preservative or antioxygen
Agent, filler, disintegrant, wetting agent, emulsifying agent, suspending agent, solvent, decentralized medium, coating agent, antibacterial agent and antimycotic
Agent, and absorption delaying agent etc..The use that such medium and medicament are used for pharmaceutically active substance is well known in the art.Except
Outside any conventional medium or reagent are incompatible with active ingredient, purposes in therapeutic combination is contemplated arrives for it.Make
For suitable therapeutic combination, the active ingredient of supplement can also be mixed in composition.
As used herein, " pharmaceutical salts " refer to the derivative of disclosed compound, and wherein parent compound is by preparing it
Acid or alkali salt and be modified.Pharmaceutically acceptable salt includes the parent compound for example formed by non-toxic inorganic or organic acid
Conventional non-toxic salts or quaternary ammonium salt.For example, such conventional non-toxic salts include being derived from inorganic acid such as hydrochloric acid, and hydrobromic acid, sulfuric acid,
Those salt of sulfamic acid, phosphoric acid, nitric acid etc.;Acetic acid, propionic acid, butanedioic acid, tartaric acid, citric acid, methanesulfonic acid, benzene sulfonic acid, Portugal
The salt of the preparations such as uronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, lactic acid.Other add
Include ammonium salt, such as tromethamine, meglumine, pentanediamine etc., metal salt such as sodium, potassium, calcium, zinc or magnesium into salt.
The pharmaceutical salts of the present invention can be by conventional chemical method by the parent compound containing alkalescence or acidic moiety
Synthesis.In general, these salt can by make these compounds free acidity or alkaline form and stoichiometry it is suitable
When prepared by reaction in the mixture of alkali or acid in water or organic solvent or both.In general, non-aqueous media such as ether, acetic acid second
Ester, ethanol, isopropanol or acetonitrile are preferable.Salt applicatory is listed in Remington's Pharmaceutical
Sciences, the 17th edition, Mack Publishing Company, Easton, PA, 1985, p.1418, the disclosure of which passes through
Reference is hereby incorporated by.
Novel conjugates disclosed herein use hydrophily connexon.Fig. 1-17 show some suitable connexons and its
The example of synthesis.
Hydrophilic link
Fig. 1-18 shows the route of synthesis for producing hydrophilic connexon and medicine and the cell-binding molecules of the present invention
The preparation of conjugate.Hydrophily chain junctor has three elements:A) it is phosphamide or phosphinates or sulfonamide, or sulfonyl,
Or sulfonamide, and/or sulfoxide, or the substituent of the mixing of these groups, b) group, such as, but not limited to can be with cell knot
The N-hydroxy-succinamide ester group of mixture reaction, maleimide base group, disulphide group, haloacetyl group, alkane
Epoxide amino group and/or hydrazides group, and c) group, such as, but not limited to, can be with the disulphide of drug response, horse
Come acid imide, haloacetyl, aldehyde, ketone, azide, amine, alkoxyamine and hydrazides.Hydrophilic substituent can pass through this paper institutes
The method stated introduces.Such as phosphamide substituent, they can be by oxygen phosphorus (V) acyl chlorides and Fig. 1, the ammonia described in 2,3,4 and 5
Base molecule direct polycondensation and formed.For phosphinate/phosphamide substituent of mixing, they can be by using Michael first
Addition handles commercially available phosphinic acids ammonium with acrylate, two excessive bromoalkanes then is substituted by phosphinate group, then
Introduced with amino-compound condensation, it is illustrated in Fig. 6,7,8 and 9., can for such as sulfonamide and sulfenamide substituent
With by chlorosulfuric acid and thionyl chloride and amino-compound direct polycondensation, as shown in Figure 10.Sulfonyl/sulfonamide substitutions base can be with
Shown by the example of the reaction of a kind of amine and chlorosulfonic acid that are condensed for example in Figure 11 and 18.The detailed conjunction of hydrophilic linkers
Into and its be used to prepare the present invention cellular binding partners-drug conjugates shown in Fig. 1~18.
Preferably, hydrophily chain junctor is the compound of lower formula (I):
Wherein:
Y represents the functional group that can be reacted with cell binding agent;
Q and T is-X1- P (=O) (OM)-, or X1-S(O2)-, or-X1–S(O)-;Or-X1- P (=O) (OM)-X2-, or-
X1- P (=O) [X2-R4-Z]-X3-, or-X1- P (=O) [X2-R1-Y]-X3-, or-X1-S(O2)-X2-, or-X1–S(O)-X2-;
X1,X2And X3Independently selected from N (R7), O, or S;In addition, work as X1It is N (R7), or during O or S, then X2Or X3It is or another
A X1With-P (=O) ,-S (O), or-S (O2) connection when, X2Or X3Or another X1Can be CH2;
M and n is the integer from 0 to 5, but cannot be 0 at the same time;
Z represents a functional group, can be by thio, thioesters, peptide, hydrazone, ether, ester, carbamate, carbonic ester, amine
(two level, three-level or level Four), imines, cycloheteroalkyl, heteroaromatic group, one cytotoxic drug of alkane oxime or acid amides key connection;
R1,R2,R3,R4,R5,R6, and R7It is, it is identical or different, it is H, the straight chained alkyl with 1-6 carbon atom, has
The side chain or cyclic alkyl of 3-6 carbon atom, straight chain, side chain or cyclic alkenyl or alkynyl, ester, ether, the acyl of 1-6 carbon atom
Amine, or molecular formula are (OCH2CH2)p, polyethyleneoxy unit, wherein p are the integers of 0 to about 1000, or combinations thereof;
M is H, or Na, or K, or N+R1R2R3Or pharmaceutical salts.Above to R1,R2And R3It is described.
In another embodiment, R1,R2,R3And R4It is the atomic link selected from C, N, O, S, Si and P respectively, it is with altogether
Valency connects cell surface binding partner, phosphinates or sulfonyl group, the medicine of coupling and (R between them1,R2, R3And R4)
Connection.Atom for forming hydrophily chain junctor can combine in a manner of all chemistry are relevant, such as form alkyl, alkene
Base, alkylidene, alkenylene and alkynylene, ether, polyoxyalkylene, ester, amine, imines, polyamines, hydrazine, hydrazone, acid amides, urea, semicarbazides, card
Bar hydrazine, alkoxyamine, carbamate, amino acid, acyloxy amine, hydroxamic acid and many other.In addition, form linking group
(L) atom either saturation can also be it is undersaturated, can be either free radical or can be cyclized to be formed each other
Bivalent cyclic structure, including cycloalkane, cyclic ethers, cyclic amine, aryl, heteroaryl etc..
The example for the functional group Y that can be reacted with cell binding agent includes amine reactant, such as, but not limited to N- hydroxyl ambers
Amber imide ester, p-nitrophenyl ester, dinitro phenyl ester, pentafluorophenyl esters;Thiol reaction agent, such as, but not limited to pyridine radicals curing
Thing, nitropyridine disulphide, maleimide, halogenated acetic acids ester and carboxylic acid chloride.
Can connect that the example of the functional group Z of cytotoxic drug includes can be via disulphide, thioether, thioesters, peptide,
The group of hydrazone, ester, carbamate, carbonic ester, alkoxy oxime or acid amides key connection.Such functional group includes but not limited to sulphur
Alcohol, disulphide, amino, carboxyl, aldehyde, dimaleoyl imino, haloacetyl, hydrazine, alkoxy amino and/or hydroxyl.
In preferred embodiments, R1,R2,R3, and R4, it is the straight chained alkyl or formula with 1-6 carbon atom
(OCH2CH2)p, p=1~100, polyethyleneoxy unit.
In another embodiment, when the hydrophilic linking group of formula (I) has two or more Y groups, particularly
During two identical Y groups, in this case, Q or/and T are-X1- P (=O) [X2-R1-Y]-X3-, then the parent of formula (I)
Water-based connector can be used for connecting two or more sites, be especially connected to the site of a pair of of cell-binding molecules.Its
Middle X1,X2And X3Independently selected from N (R7),O,CH2Or S;R1It is as defined above face.
In another embodiment, when the hydrophily chain junctor of formula (I) has two or more Z groups, at this
In the case of kind, Q or/and T are-X1- P (=O) [X2-R4-Z]-X3-, then the hydrophilic linkers of formula (I) can be used for connecting
Two or more medicines, particularly two kinds of different medicines.Wherein X1, X2And X3Independently selected from N N (R7),O,CH2Or S;
R4 is as defined above face.
Formula (I) containing 2- bis- it is thio-the synthesis example of the cross linked chain junctor of the pyridine radicals institute in Fig. 2,6,9,11 and 12
Show.The synthesis example of the cross linked chain junctor containing dimaleoyl imino of formula (I) institute in Fig. 1,3,4,5,7,8,10,13 and 17
Show.The synthesis example of the Sulfide-containing Hindered cross linked chain junctor of formula (I) is shown in Fig. 1,3,4,5,7,8,10,12 and 17.Formula (I's) contains
There is the synthesis example child of hydrophilic cross-linking chain junctor of polyethylene glycol in Fig. 7,8,9,11,12,13,14,15,16,17 and 18
It is shown.Hydrophilic cross-linking chain junctor of the formula (I) containing azide is arrived for Huisgen 1,3- dipole-diople interaction azide
The example of the synthesis containing azide of (also referred to as click chemistry) is shown in Fig. 8,9,13 and 18 on alkynes.With can lead to
The synthesis example of the hydrazides of peracid labile bond connection or the hydrophilic cross-linking chain junctor of the formula of ketone or alkoxy portion (I) is being schemed
Shown in 6,9,11,14,15 and 16.Synthesis can each chain junctor connects two medicines or each attachment connects two sites
The example of hydrophilic connector of formula (I) shown in Fig. 1,2,3,4,5,6,7,17 and 18.Synthesis can each chain junctor connect
The example for connecing the hydrophilic connector of the formula (I) of two different compound/medicines is shown in Fig. 8,9,11,14,15,16 and 17.
Synthesis can each formula (I) of chain junctor one cytotoxic compound of connection and a chromophore molecule hydrophilic connector
Example is shown in fig. 13.
Cell binding agent-drug conjugates titer
The conjugate of the present invention can be by following formula Cb- (- L-Drug)n, represent, wherein Cb is cell binding agent, and L is hydrophilic
Property chain junctor, Drug is drug molecule, and n is the integer from 1 to 20.
Hydrophilic linkers L can contain by one or more connector components.Such as component include 6- maleimides
Caproyl (" MC "), maleimide propiono (" MP "), valine-citrulline (" val-cit " or " vc "), alanine-benzene
Alanine (" ala-phe " or " af "), 4- aminobenzyloxycarbonyls (" PAB "), the thio valerates of 4- (" SPP "), 4- (N- Malaysias acyls
Formimino group) carboxylate of hexamethylene -1 (" MCC "), 4- acetaminobenzoic acids ester (SPO), the thio -2- hydroxysufonyls-fourths of 4-
Acid esters (2- sulfo groups-SPDB), ethyleneoxy-- CH2CH2O- is as one or more repetitive units (" EO " or " PEO ").Other chains
Junctor component is well known in the art, and some chain junctor groups are described herein.
The exemplary construction of these components for containing chain junctor is:
(MC, maleimidocaproyl containing 6-)
(MP, propiono containing dimaleoyl imino)
(PAB, containing to aminobenzyloxycarbonyl)
(ME, containing maleimidoethyl)
(containing valine-citrulline)
(MCC, 4- (N- maleimidomehyls) carboxylate of hexamethylene -1)
((4- acetyl group) Aminobenzoate)
(thio -2- hydroxysufonyls-butyrates of 4-, 2-Sulfo-SPDB)
Preferably, conjugate has lower formula (II):
Wherein:
Cb represents cell binding agent;
Drug represent medicine be according to alkyl, alkylidene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imines, it is more
Amine, hydrazine, hydrazone, acid amides, urea, semicarbazides, carbonohydrazides, alkoxyamine, polyurethanes, amino acid, peptide, acyloxy amine are different
Hydroximic acid, disulphide, thioether, thioesters, carbamate, carbonic ester, heterocycle, miscellaneous alkyl, heteroaryl or alkane oxime key or they
The push-to of combination cross hydrophily chain junctor and be connected with cell binding agent.
Q is 1~30;M, n, R1,R2,R3,R4,R5,R6It is identical with the description in foregoing formula (I) with M.
Q and T is-X1- P (=O) (OM)-, or-X1-S(O2)-, or-X1–S(O)-;Or-X1- P (=O) (OM)-X2-, or-
X1- P (=O) [X2-R4-Drug]-X3-, or-X1- P (=O) [X2-R1-Cb]-X3-, or-X1-S(O2)-X2-, or-X1–S(O)-
X2-;Wherein X1, X2And X3It is identical with described in formula (I).
In another embodiment, when the conjugate of formula (II) has two or more Cb groups, particularly two
During identical Cb groups, in this case, Q or/and T are-X1- P (=O) [X2-R1-Cb]-X3-, then the conjugate of formula (II)
Two or more sites are connected to, the site of particularly a pair of of cell-binding molecules.
In another embodiment, when the conjugate of formula (II) has two or more Drug groups, this
In the case of, Q or/and T are-X1- P (=O) [X2-R4-Drug]-X3-, then the conjugate of formula (II) and two or more medicines
Connection, particularly two or more different medicines.
As described in more detail below, medicine can be any one of many small-molecule drugs, include but not limited to
Tubulysins, Cali's miramycin, auspicious statin difficult to understand, maytansine, CC-1065 derivatives, morpholine Doxorubicin, taxol are hidden
Phycomycete element, Epothilones and Benzodiazepine dimer (such as pyrroles's Benzodiazepine dimer, tomaymycin dimer, indoline
Benzodiazepine dimer, imidazoles Benzodiazepine dimer, oxazoline Benzodiazepine dimer) class.
For synthesis of coupling thing, cell binding agent can be modified to introduce with the hydrophily chain junctor of the present invention first
The reactivity of disulphide, dimaleoyl imino, haloacetyl, azide, 1- alkynes, ketone, aldehyde, alkoxy amino or hydrazides
Group.Be synthesized by the cell binding agent of modification the two of the Cell binding agent-drug conjugates titer connected by disulfide bond
Disulfide bond between sulfide linkage and the medicine containing free sulfhydryl groups exchanges to realize.Cell binding agent-the medicine connected by thioether
The cell binding agent that the synthesis of thing conjugate is modified by dimaleoyl imino or haloacetyl or ethylsulfonyl is with containing
The reaction of the medicine of free sulfhydryl groups is realized.The synthesis of conjugate with the unstable hydrazone key of acid can be by known in the art
Method realized according to the reaction of the hydrazides part in carbonyl and chain junctor (see, for example, P.Hamann et al., Cancer
Res.53,3336-334,1993;B.Laguzza et al., J.Med.Chem., 32;548-555,1959;P.Trail etc.,
Cancer Res., 57;100-105,1997).
Furthermore it is possible to the present invention hydrophilic linkers medicine is modified, with obtain have can be with cell knot
The modified medicaments of the formula (IV) of the function of mixture reaction.For example, the medicine containing sulfydryl can with maleimide, halo second
The hydrophily linker of the formula of acyl group or ethylsulfonyl substituent (I) is reacted in neutral pH aqueous buffer solution, is obtained according to sulphur
The medicine of ehter bond connection hydrophily chain junctor connection.Medicine containing mercaptan can be with the hydrophily with dialkyl dithio part
Chain junctor carries out disulfide exchange, so as to obtain the modification of pharmaceutical being connected by disulfide bond with hydrophilic cross-linking chain junctor.Tool
The medicine of hydroxyl or sulfydryl can react in the presence of gentle alkali with the hydrophilic linker with halogen of the invention, obtain
Modification of pharmaceutical with ether or mercaptan ehter bond.Medicine containing hydroxyl can be in the presence of dehydrating agent such as EDC or DCC with carrying
The hydrophilic cross-linking chain junctor condensation of the formula (I) of carboxyl, obtains ester bond modification of pharmaceutical.Amino-containing medicine can similarly with formula
(I) the carboxyl on hydrophilic linkers is condensed and obtains amido link link.
Conjugate can be by the biochemistry means of standard as on Sephadex G25 or Sephacryl S300 columns
Gel filtration, adsorption chromatography and ion exchange are purified by dialysing.In some cases, it is small with small-molecule drug coupling
Molecule as cell binding agent (such as folic acid, melanophorin, EGF etc.) can by chromatography such as HPLC, medium pressure column chromatography or
Ion-exchange chromatography purifies.
The cell binding agent of modification
By being preferable over formula (III) with the cell binding agent for linking precursor reactant to modify of the present invention
[01] wherein Cb, q, m, n, R1,R2,R3,R4,R5,R6With Z and substituent therein and foregoing formula (I) and (II)
In description it is identical.
Q and T is-X1- P (=O) (OM)-, or-X1-S(O2)-, or-X1–S(O)-;Or-X1- P (=O) (OM)-X2-, or-
X1- P (=O) [X2-R4-Z]-X3-, or-X1- P (=O) [X2-R1-Cb]-X3-, or-X1-S(O2)-X2-, or-X1–S(O)-X2-;
Wherein X1,X2And X3It is identical with described in formula (I).
In another embodiment, when the compound of formula (III) has two or more Cb groups, particularly two
During identical Cb groups, in this case, Q or/and T are-X1- P (=O) [X2-R1-Cb]-X3-, then the change of formula (III)
Compound connects two or more sites, the site of particularly a pair of of cell-binding molecules.
In another embodiment, when the compound of formula (III) has two or more Z groups, in this feelings
Under condition, Q or/and T are-X1- P (=O) [X2-R4-Z]-X3-, then the compound of formula (III) can be used for connecting two or more
Kind medicine, particularly two kinds of different medicines.
In preferred embodiments, Z is disulphide substituent, dimaleoyl imino, haloacetyl, alcoxyl amine
Base, diazanyl or N-hydroxy-succinamide ester base group, and R1With Cb through thioether, hydrazone, acid amides, alkane oxime, carbamate or
Disulfide bond connects.The cell binding agent of modification can be prepared by the reaction of cell binding agent and hydrophily chain junctor.These methods
The other cross linked chain junctors in this area method prepare in it is known that (U.S. Patent number 5,846,545,5,585,499,5,
475,092,5,414,064,5,208,020,and 4,563,304;The ..Biochem.J. such as Carlsson, J. (1978) 173,
723-737(1978);Goff,D.A.,Bioconj.Chem.(1990),1,381-386;L.Delprino etc.
.J.Pharm.Sci.(1993),82,506-512;S.Arpicco etc., Bioconjugate Chem (1997), 8,327-
337).
Advantageously, because the phosphamide on hydrophily chain junctor, phosphinates, sulfonamide, sulfonyl, sulfimide
And/or sulfoxide radicals are water-soluble or only need the organic solvent of small percentage to maintain solubility in aqueous, cell
Bonding agent and chain junctor can carry out in aqueous.Chain junctor is dissolved in containing a small amount of (usual<10 volume %) can be with water
Miscible polar organic solvent (such as different alcohol such as methanol, ethanol and propyl alcohol), acetone, acetonitrile, tetrahydrofuran (THF), 1,
In the water buffer solution of 4- dioxanes, dimethylformamide (DMF), dimethylacetylamide (DMA) or dimethyl sulfoxide (DMSO) (DMSO)
Up to high concentration, such as 1-100mM, then to add in the aqueous buffer solution of appropriate aliquot cell binding agent.It is suitable etc.
1-10 chain junctor group is introduced with each cell binding agent in point sample solution, preferably 1-6 chain junctor group, and
10%, preferably 5%, the volume of the cell combination agent solution of most preferably 0-3% is not to be exceeded in volume to be added.Cell combination
The aqueous solution of agent is buffered between pH 6 and 9, preferably between 6.5 and 7.5, and can be to these pH models containing any
The non-nucleophilic buffer salt being with.Typical buffer includes phosphate, triethanolamine HCl, HEPES and MOPS buffer,
They can contain other components, such as cyclodextrin, sucrose and salt, such as NaCl and KCl.After addition, it will react at 4 DEG C to 45
At a temperature of DEG C, preferably incubate at ambient temperature.The process of reaction can be appropriate in 280 or 320nm or another by measurement
The increase of absorption under wavelength monitors.After the completion of reaction, usual manner such as gel filtration chromatography or adsorption chromatography can be used
The cell binding agent of method separation modification.
The degree of modification can be by measuring the N- oxo pyridine thioketones discharged, di nitryl pyridine dithione, pyridine sulphur
The absorbance of ketone, formamido group pyridine dithione and diformamide yl pyridines dithione group is assessed.It is described herein hydrophilic
Property chain junctor there is different functional groups, it can be reacted with any cell binding agent with suitable substituent.Such as with
The cell binding agent of amino or hydroxyl substituent can be anti-with the cross linked chain junctor with n-hydroxysuccinimide (NHS) ester
Should, the cell binding agent with thiol substituent can be anti-with the cross linked chain junctor with dimaleoyl imino or haloacetyl
Should.In addition, the cell binding agent with carbonyl substituent can be with linking precursor reactant with hydrazides or alkoxyamine.This area
Technical staff can the known response of functional group is relatively easily definite to be linked using for which based on that can be used on cell binding agent
Body.
Modified cells cytotoxic drug
Formula (IV) is preferable over by the cytotoxic drug reacted with the cross linked chain junctor of the present invention to modify:
Wherein Y, m, n, R1,R2,R3,R4,R5,R6And the substituent in medicine, and formula (IV) such as foregoing formula (I) and
(II) described in.
Q and T is-X1- P (=O) (OM)-, or-X1-S(O2)-, or-X1–S(O)-;Or-X1- P (=O) (OM)-X2-, or-
X1- P (=O) [X2-R4-Drug]-X3-, or-X1- P (=O) [X2-R1-Y]-X3-, or-X1-S(O2)-X2-, or-X1–S(O)-
X2-;Wherein X1, X2And X3It is identical with described in formula (I).
In another embodiment, when there is two or more Y groups in the compound of formula (IV), particularly two phases
With Y group when, in this case, Q or/and T are-X1- P (=O) [X2-R1-Y]-X3-, then the compound of formula (IV) can
Two or more sites are connected to, the site of particularly a pair of of cell-binding molecules.
In another embodiment, when the compound of formula (IV) has two or more Drug groups, this
In the case of, Q or/and T are-X1- P (=O) [X2-R4-Drug]-X3-, then the compound of formula (II) and two or more medicines
Connection, particularly connects two or more different medicines.
In preferred embodiments, Y is disulphide substituent, dimaleoyl imino, haloacetyl, alkoxy ammonia
Base, carboxylic acid or N-hydroxy-succinamide ester.
Modified medicaments can by preparing medicine and the connection precursor reactant of the present invention so that obtain having can with it is thin
The modified medicaments of the formula (IV) of the function of born of the same parents' bonding agent reaction.For example, the medicine containing sulfydryl can be with taking with maleimide
The chain junctor of the formula (I) of Dai Ji reacts in water-containing buffering liquid under neutral ph, obtains being connected to hydrophily chain by thioether bond
The medicine of junctor.Medicine containing sulfydryl can carry out disulphide friendship with the hydrophily chain junctor with dialkyl dithio part
Change, obtain the modified medicaments being connected by disulfide bond with hydrophily chain junctor.Medicine with hydroxyl can be in the presence of weak base
With the connection precursor reactant with halogen, the medicine of the modification with ehter bond is obtained.In dehydrating agent such as EDC or dicyclohexyl carbonization two
In the presence of imines (DCC), the medicine of hydroxyl can be condensed with the linker of the formula (I) with carboxyl, obtain ester bond.Have
The medicine of sulfydryl can be reacted with the linker with dimaleoyl imino or vinylsulfonyl or haloacetyl, obtain band
There is the medicine of the modification of thioether bond.Amino-containing medicine can be carried out similarly with the carboxyl on the hydrophilic linkers of formula (I)
It is condensed and obtains the medicine of the modification of amido link.The medicine of modification can pass through the column color in standard method such as silica gel or aluminium oxide
Spectrum, crystallization, prepares thin-layer chromatography, ion-exchange chromatography or HPLC to purify.
Cell binding agent
The conjugate of cell-binding molecules construction of the present invention and being currently known for the cell binding agent of modification
Or combine a part for any kind of and cell mass known, compound or reaction molecule, this molecule can be treated or it
Allogene is modified on learning.
Cell binding agent includes but not limited to large molecular weight protein, such as (polyclonal antibody, monoclonal resist full length antibody
Body, dimer, polymer, multi-specificity antibody (such as bispecific antibody), single-chain antibody;Such as Fab, Fab', F
(ab')2,Fv, the antibody fragment of [Parham, J.Immunol.113,2895-2902 (1983)], is produced by Fab expression libraries
Fragment, specifically binds cancer cell antigen, viral antigen, microbial antigen or can identify by immune system generation, with reference to
Protein any of the above-described kind of antiidiotype (anti-Id) antibody, CDR and epitope binding fragments (Miller et al
(2003)J.of Immunology 170:4854-4861);Interferon (such as I, II, type III);Peptide;Lymphokine such as IL-2,
IL-3, IL-4, IL-5, IL-6, IL-10, GM-CSF, interferon-γ (IFN-γ);Hormone such as insulin, TRH (melanotropin
Releasing hormone), MSH (melanocyte-stimulating hormone(MSH)), steroid hormone such as androgen and estrogen, melanophorin (MSH);
Epidermal growth factor (EGF), granulocyte macrophage colony stimulating factor (GM-CSF), transforming growth factor (TGF) such as TGFα,
The growth factors such as TGF β, insulin and insulin-like growth factor (IGF) and colony stimulating factor-I, IGF-II) G-CSF, M-
CSF and GM CSF [Burgess, Immunology Today, 5,155-158 (1984)];Vaccinia growth factor (VGF);Into fibre
Tie up Porcine HGF (FGF);The protein of relatively small molecular weight, polypeptide, peptide and peptide hormone, such as bombesin, gastrin, gastrin
Release peptide;Platelet-derived growth factor;Interleukin 2 (IL-2), interleukin-6 (IL-6), leukaemia suppress
Interleukins and the cell factor such as the factor, granulocyte macrophage colony stimulating factor (GM-CSF);Vitamin, such as folic acid;
De- albumen and glycoprotein, such as transferrins [O'Keefe etc., 260J.Biol.Chem.Chemistry.932-937(1985)];Sugar knot
Hop protein or lipoprotein, such as agglutinin;Cytotrophy transmits molecule;Such as prostate-specific membrane antigen (PSMA) inhibitor
With small molecule tyrosine kinase inhibitors (TKI), non-peptide or any other cell-binding molecules or material such as bioactive polymerization
The micromolecular inhibitor (Dhar, et al., Proc.Natl.Acad.Sci.2008,105,17356-61) of thing;Bioactivity is tree-shaped
Aggressiveness (Lee, etc. Nat.Biotechnol.2005,23,1517-26;Almutairi, etc.;
Proc.Natl.Acad.Sci.2009,106,685-90);Nano particle (Liong etc., ACS Nano, 2008,19,1309-
12;Medarova etc., Nat.Med.2007,13,372-7;Javier etc., Bioconjugate Chem.2008,19,1309-
12);Liposome (Medinai et al., Curr.Phar.Des.2004,10,2981-9);Viral capsid (Flenniken etc.,
Viruses Nanotechnol.2009,327,71-93)。
In general, if it is appropriate it is optional if, preferred monoclonal antibody is as cell surface binding agent.Antibody can be with
It is muroid, the mankind, humanization is fitted together to or the antibody derived from other species.
Production for the antibody of the present invention is related to inner or in vitro program or its combination carries out.Produce Anti-TNF-α acceptor
The method of peptide antibody is well known in the art, such as United States Patent (USP) 4,493,795 (authorizing Nestor et al.).Usually by by bone
The splenocyte of mouse of the myeloma cells with being immunized come antigen needed for using by oneself merge prepare monoclonal antibody (G.;
Milstein, C. (1975) .Nature 256:495-497).In the Cold Spring Harbor that Harlow and Lane are edited
Laboratory Press, New York's (1988) " describes in detail in Antibodies-A Laboratory Manual "
Program, the document is hereby incorporated by reference.Especially, monoclonal antibody by using required research for example complete target of antigen
Cell, from the separated antigen of target cell, totivirus, mouse, rat, hamster or any is immunized in the totivirus and virus protein of attenuation
Other mammals produce.Splenocyte is merged with myeloma cell usually using polyethylene glycol (PEG) 6000.By right
The sensitive Sexual behavior mode fusion hybrid of HAT (hypoxanthine-aminopterin-thymidine).Produce and can be used for implementing the present invention's
The hybridoma of monoclonal antibody is reflected by the ability of the receptor active in its specific receptor immune response or suppression target cell
It is fixed.
Monoclonal antibody for the present invention can be by starting the monoclonal for including the nutrient medium containing hybridoma
Hybridoma culture produces, the antibody molecule of the hybridoma secretion with appropriate antigentic specificity.It is being enough to make hybridoma
Culture is kept under conditions of antibody molecule is secreted into culture medium.Then the culture medium containing antibody is collected.It can then lead to
The further isolated antibody of known technology is crossed, such as uses protein-A affinity chromatographys;Anion, cation, hydrophobicity
Or size exclusion chromatography (especially by the affinity and size exclusion column chromatography of the specific antigen after a-protein);
Centrifugation, differential solubility, or pass through any other standard technique for protein purification.
It is well known in the present art available for the culture medium for preparing these compositions and commercially available acquisition, including
Synthetic media.Exemplary synthetic media is Dulbecco's extremely dulbecco minimum essential medium Dulbecco (DMEM;Dulbecco etc.,
Virol.8,396 (1959) are supplemented with 4.5g/l glucose, 0-20mM glutamine, 0-20% hyclones, the weight of several ppm
Metal such as Cu, the heavy metal such as Mn, Fe or Zn or/and with its salt form add, and with defoamer such as polyoxyethylene-polyoxy third
The amount of alkene block copolymer.
In addition, antibody-producting cell system can also be produced by the technology beyond fusion, such as directly converted with carcinogenic DNA
Bone-marrow-derived lymphocyte, or with such as Epstein-Barr virus (EBV, also referred to as human herpesvirus 4 (HHV-4)) or Kaposi sarcoma associated herpes
Viral (KSHV) transfection.Referring to US patent number 4,341,761;4399121;4427783;4,444,887;
4451570;4,466,917;4472500;4491632;4493890.Monoclonal antibody can also be as known in the art
Produced by anti-acceptor peptide or peptide containing carboxyl terminal.Referring to Niman et al., Proc.Natl.Acad.Sci.USA, 80:
4949-4953(1983);Geysen et al., Proc.Natl.Acad.Sci.USA, 82:178-182(1985);Lei et al.
.Biochemistry 34(20):6675-6688,(1995)..In general, anti-acceptor peptide or peptide analogues are used alone or with exempting from
Epidemic focus carrier conjugation, as the immunogene for producing anti-acceptor peptide monoclonal antibody.
There are many other well-known technologies for being used to prepare monoclonal antibody as binding molecule in the present invention.
It is especially useful that the method for preparing fully human antibodies.A kind of method is display technique of bacteriophage, it is used for affine
The method of enrichment selects the series of human antibody combined with antigentic specificity.Existing document has fully described phage display technology
Show, and the construction and screening of phage display library is well known in the present art, see, for example, Dente et al.,
Gene.148(1):7-13(1994);Little et al., Biotechnol Adv.12 (3):539-55(1994);Clackson
Et al., Nature 352:264-628(1991);Huse et al., Science 246:1275-1281(1989).
By the monoclonal antibody of another species such as mouse-derived of the hybridoma technology beyond people can be humanized with
Avoid human anti-mouse antibody caused by people's infusion.The more conventional method of antibody humanization is complementary determining region transplanting and surface weight
Build.These methods have been widely described, see, for example, US patent number 5,859,205 and 6,797,492;Liu
Et al., Immunol Rev.222:9-27(2008);Almagro et al., Front Biosci.13:1619-33(2008);
Lazar et al., Mol Immunol.44 (8):1986-98(2007);Li et al. people, Proc.Natl.Acad.Sci.U S are A.103
(10):3557-62 (2006), each piece is contained by it to be incorporated herein by reference.Fully human antibodies can also be by using immunogene
Immunizing transgenic mice, rabbit or carry other mammals of most people's heavy chain immunoglobulin and light chain to make at monkey
It is standby.The example of this mouse is:Xenomouse. (Abgenix/Amgen), HuMAb- mouse (Medarex/BMS),
VelociMouse (Regeneron) United States Patent (USP) 6,596,541,6,207,418,6,150,584,6,111,166,6,075,
In 181,5,922,545,5,661,016,5,545,806,5,436,149 and 5,569,825., can also in being treated to people
By mouse variable region and human constant region fusion to build the construct of referred to as " chimeric antibody ", its immunogenicity in people compares mouse
Much lower (Kipriyanov etc., the Mol Biotechnol.26 of mAb:39-60(2004);Houdebine, Curr Opin
Biotechnol.13:625-9 (2002), is hereby incorporated by reference per text).In addition, the direct mutagenesis in antibody variable region can
Cause that there is more high-affinity and specific antibody (Brannigan et al., Nat Rev Mol Cell to its antigen
Biol.3:964-70, (2002));Adams et al., J Immunol Method.231:249-60 (1999)), and exchange
The constant region of mAb can improve the ability of the effector function of its mediation combination and cytotoxicity.
The antibody for having immunologic opsonin to malignant cell antigen can also be commercially-available or passes through those skilled in the art
Any known method such as chemical synthesis or recombination and expression techniques obtain.There is immunologic opsonin to malignant cell antigen
The nucleotide coding sequence of antibody commercially available can obtain, such as from GenBank databases or its similar database, document
Publication, or obtained by routine cloning and sequencing.
In addition to antibody, can combine/blocking/targeting or in some other manner to the epitope on target cell or corresponding
The peptide or protein matter of acceptor interaction can be used as binding molecule.These peptide or protein matter can be to epitope or corresponding acceptor tool
There is any random peptide or protein matter of affinity, and they not necessarily must belong to immunoglobulin class.These peptides can be with
(Szardenings, J Recept Signal Transduct are separated by the technology similar with phage displaying antibody
Res.2003;23(4):307-49).The use of peptide from this random peptide library can be similar to antibody and antibody fragment.
The binding molecule of peptide or protein matter can be combine or be coupled on macromolecular or material or with macromolecular or material, such as but
Albumin, polymer, liposome, nano particle, dendrimer are not limited to, as long as this combination allows peptide or protein quality guarantee to stay it
Antigen-binding specificity.
It is used for what is be coupled with medicine by hydrophilic chain in the present invention, for treating cancer, autoimmune disease and sense
The antibody citing of infectious diseases, but not limited to this, it is as follows:3F8 (anti-GD2 antibody), A Bafu monoclonal antibodies (anti-CA-125 antibody), Ah
(anti-CD41 antibody (integrin alpha-IIB), adalimumab (anti-TNF-Alpha antibodies), (anti-EpCAM resists A De wood monoclonal antibody former times monoclonal antibody
Body, CD326), Afelimomab (anti-TNF-α);Ah husband's soil pearl (anti-CD 20 antibodies), Alacizumab pegol are (anti-
VEGFR2 antibody), ALD518 (anti-IL-6 antibody), alemtuzumab (alias:Campath, MabCampath, Alemtuzumab, resists
CD52 antibody), Altumomab (CEA antibodie), Anatumomab (anti-TAG-72 antibody), Anrukinzumab (alias:
IMA-638, anti-IL-13 antibody), Ah Bo pearl monoclonal antibody (anti-HLA-DR antibody), Arcitumomab (CEA antibodie), A Saizhu
Monoclonal antibody (anti-L-selectin (CD62L) antibody, Atlizumab (alias:Torr pearl monoclonal antibody, Actemra, RoActemra, anti-IL-6
Receptor antibody), Atorolimumab (anti-rh factor antibody), bapineuzumab (anti-β-amyloid), bar
(Shu Lai, antiCD25 (the α chains of IL-2 acceptors) antibody, Ba Wei former times monoclonal antibody (anti-phosphatidylserine antibody), shellfish is appropriate for sharp former times monoclonal antibody
Not monoclonal antibody (alias:LymphoScan, anti-CD22 antibody), Baily wood monoclonal antibody (alias:Benlysta, LymphoStat-B, resist
BAFF antibody), Benralizumab (anti-CD125 antibody), cypress replace wooden monoclonal antibody (anti-CCL11 (eosinophil chemokine-
1) antibody), shellfish rope monoclonal antibody (alias:Scintimun, anti-CEA- associated antigens), bevacizumab (alias:Avastin, resists
VEGF-A antibody) Biciromab (alias:FibriScint, II β chain antibodies of antiplasmin), Bivatuzumab is (anti-
CD44v6 antibody), blinatumomab (alias:BiTE, anti-CD 19 antibodies), and Brentuximab (CAC10, it is anti-
CD30TNFRSF8 antibody), Briakinumab (anti-IL-12, IL-23 antibody), Kang Na monoclonal antibody (alias:Ilaris, anti-IL-1
Antibody), Cantuzumab (alias:C242, anti-CanAg antibody), Capromab, catumaxomab (alias:Removab, resists
EpCAM, anti-CD 3 antibodies), CC49 (anti-TAG-72 antibody), Cedelizumab (anti-CD 4 antibodies), match trastuzumab (alias
Cimzia anti-TNF-α antibodies), Cetuximab (alias:Erbitux, IMC-C225, anti-EGFR-antibodies), his native pearl of west is (anti-
EpCAM antibody), Cixutumumab (anti-IGF-1 antibody), clenoliximab (anti-CD 4 antibodies), Clivatuzumab is (anti-
MUC1 antibody), Conatumumab (anti-TRAIL-R2 antibody), CR6261 (anti-A type influenza hemagglutinin antibody), Dacetu-
Zumab (anti-CD 40 antibodies), daclizumab (alias:Zenapax, anti-CD25 (the α chains of IL-2 acceptors) antibody),
Daratumumab (anti-cd 38 (cyclisation ADP ribose hydrolase) antibody), Di Nuosaimai (alias:Prolia, anti-RANKL resist
Body), Detumomab (anti-B- lymphoma cells antibody), Dorlimomab Aritox, Dorlixizumab, Ecromeximab (anti-GD3 god
Warp knuckle glycosides fat antibody), Yi Kuli monoclonal antibody (alias:Soliris, anti-C5 antibody), Edobacomab (anti-endotoxin antibody), according to certainly
Lip river monoclonal antibody (alias:Panorex, MAb17-1A, anti-EpCAM antibody), efalizumab (alias:Raptiva, anti-LFA-1
(CD11a) antibody), Yi Fengu monoclonal antibody (alias:Mycograb, anti-Hsp90 antibody), Elotuzumab (anti-SLAMF7 antibody),
Yi Silimo (anti-IL-6 antibodies), Enlimomab (anti-ICAM-1 (CD54) antibody), (anti-episialin resists Epitumomab
Body), epratuzumab (anti-CD22 antibody), Erlizumab (anti-ITGB2 (CD18) antibody), Ertumaxomab (alias:
Rexomun, anti-HER2/neu, CD3 antibody), Yi Ruixi pearl (alias:Abegrin, anti-integrin alpha v beta 3 antibody), Ai Wei monoclonal antibodies
(anti-HBs antibody), Fanolesomab (alias:NeutroSpec, anti-CD15 antibody), faralimomab
(anti-interferon receptor antibody), Farletuzumab (anti-1 antibody of folacin receptor), Felvizumab (anti respiratory syncytial virus
Antibody), Fezakinumab (anti-IL-22 antibody), Figitumumab (anti-IGF-1 receptor antibodies), Fontolizumab are (anti-
IFN-γ antibody), such as (Antibody against the glycoprotein of rabies viruse), Fresolimumab (anti-TGF-beta antibodies), adds sharp former times single to Fu Ruiwei
Anti- (Anti-CD80 McAb), Gantenerumab (anti-beta amyloid antibody), Gavilimomab (anti-CD14s 7 (basigin)
Antibody), WAY-CMA 676 (anti-CD 33 antibody), Girentux-imab (anti-9 antibody of carbonic anhydrase), Glembatumumab 5 are (not
Name:CR011, anti-GPNMB antibody), goli mumab (alias:SIMPONI, anti-TNF-α antibody), Gomiliximab (anti-CD23
(IgE acceptors) antibody), Ibalizumab (anti-CD 4 antibodies), ibritumomab tiuxetan (anti-CD 20 antibodies), Igovomab (alias:
Indimacis-125, anti-CA-125 antibody), Imciromab (alias:Myoscint, anti-Cardiac Myosin antibody), Ying Fuli
Former times monoclonal antibody (alias:Infliximab, anti-TNF-α antibody), Intetu-mumab (anti-CD51 antibody), Inolimomab (resists
CD25 (IL-2 receptor alpha chains) antibody), Inotu-zumab (anti-CD22 antibody), easy Puli's nurse agate (anti-CD152 antibody),
Iratumumab (AntiCD3 McAb 0 (TNFRSF8) antibody), Keliximab (anti-CD 4 antibodies), Labetuzumab (alias:CEA-
Cide, CEA antibodie), (anti-NCA-90 (G-Ag) is anti-by Lebrikizumab (anti-il-13 antibody), Lemalesomab
Body), happy moral wood monoclonal antibody (anti-TGF β -2 antibody), comes husky wooden monoclonal antibody (2 antibody of anti-TRAIL-R), sharp Wei Dankang (resistance of hepatitis B tables
Face antigen-antibody), lintuzumab (anti-CD 33 antibody), Lucatumumab (anti-CD 40 antibodies), Shandong former times monoclonal antibody (anti-CD23
(IgE acceptors) antibody), Mapa-tumumab (1 antibody of anti-TRAIL-R), Maslimomab (anti-T-cell receptors antibody), horse is appropriate
Pearl monoclonal antibody (anti-EGFR-antibodies), mepolizumab (alias:Bosatria, anti-IL-5 antibody), Metelimumab (anti-TGF β -1
Antibody), Milatuzumab (anti-CD74 antibody), Minretumomab (anti-TAG-72 antibody), mitumomab (alias BEC-
2, anti-GD3 ganglioside antibodies), Morolimumab (anti-rh factor antibody), does not tie up pearl monoclonal antibody (alias:NUMAX,
Anti respiratory syncitial virus antibodies), muromonab-CD3 (alias:OKT3ORTHOCLONE, anti-cd 3 antibodies), Nacolomab tafenatox
(anti-C242 antibody), Ta Namo monoclonal antibodies (anti-5T4 antibody), natalizumab (alias:Tysabri, anti-4 antibody of integrin alpha), how
25 monoclonal antibody of Baku (anti-endotoxin antibody), Necitumumab (anti-egfr antibodies), Nere-limomab (anti-TNF-α antibody), Buddhist nun
Trastuzumab (alias:Theracim, Theraloc, anti-egfr antibodies), (anti-CD20 resists by Nofetumomab, ocrelizumab
Body), Odulimomab (alias:Afolimomab, anti-LFA-1 (CD11A) antibody), wooden monoclonal antibody (alias:Arzerra, anti-CD20
Antibody), Olaratumab (anti-PDGF-R Alpha antibodies), omalizumab (alias:Sorel, anti-IgE Fc domain antibodies),
Oportuzumab (anti-EpCAM antibody), Ao Gefu monoclonal antibody (alias:OvaRex, anti-CA-125 antibody), Otelixizumab is (anti-
CD3 antibody), pa Ji former times monoclonal antibody (anti lipoteichoic acid antibody), palivizumab (alias:Synagis, Abbosynagis, it is anti-to exhale
Inhale road syncytial virus antibody), Victibix (alias:Wei Ke is replaced than, ABX-EGF, anti-EGFR-antibodies), Panobacumab is (anti-
Pseudomonas aeruginosa antibody), Pasco-lizumab (anti-IL-4 antibody), Pemtumomab (alias:Theragyn, anti-MUC1 antibody),
Handkerchief trastuzumab (alias:OMNITARG, 2C4, anti-HER2/neu antibody), training gram pearl monoclonal antibody (anti-C5 antibody), Pintumomab
(anti-gland cancer antigen-antibody), priliximab (anti-CD 4 antibodies), general bolster monoclonal antibody (anti-vimentin antibodies), PRO140 are (anti-
CCR5 antibody), Racotumomab (alias:1E10, anti-(NeuGc ALPHA2-3Gal (NeuGc, NGNA)-gangliosides
GM3) antibody), Rui Feiweilu (Antibody against the glycoprotein of rabies viruse), Ramucirumab (anti-vegf R2 antibody), Lucentis
(alias:Lucentis, anti-vegf-A antibody), Rui Xi Bakus (anti-anthrax toxin, protective antigens antibody), regavirumab
(the Glycoprotein B antibody of anti-cytomegalovirus), Reslizumab (anti-IL-5 antibody), Rilotumumab (anti-HGF antibody), profit
Appropriate former times monoclonal antibody (alias:Mabthera, Rituxanmab, anti-CD 20 antibodies), Robatumumab (anti-IGF-1 receptor antibodies),
Rontalizumab (anti-ifn-alpha antibody), Rovelizumab (alias:LeukArrest, anti-CD11, CD18 antibody),
Ruplizumab (alias:Antova, anti-CD154 (CD40L) antibody), Satumomab (anti-TAG-72 antibody), Sevirumab
(anti-cytomegalovirus antibody), Sibrotuzumab (anti-FAP antibody), Sifalimumab (anti-ifn-alpha antibody),
Siltuximab (anti-IL-6 antibodies), Siplizumab (anti-CD2 antibody), (Smart) MI95 (anti-CD 33 antibody),
Solanezumab (anti-β-amyloid), Sonepcizumab (anti-sphingosine -1- phospho-ABs), Suo Tuzhu
Monoclonal antibody (anti-episialin antibody), Si Tamolu (anti-myostatin antibody), sulesomab (alias:LeukoScan,
(anti-NCA-90 (G-Ag) antibody))), Tacatuzumab (Anti-α-Fetoprotein antibody), he spends (the anti-integration of pearl monoclonal antibody
Plain 3 antibody of α IIb β), his sharp pearl monoclonal antibody (anti-IgE antibodies), his Buddhist nun pearl (anti-ngf antibodies), (anti-CD19 resists Taplitumomab
Body), Tefibazumab (alias:Aurexis, resistant to aggregation factors A antibody), Telimomab Aritox, Tenatumomab (anti-solid raw eggs
White C antibody), for how former times monoclonal antibody (anti-CD 40 antibodies), Teplizumab (anti-cd 3 antibodies), TGN1412 (anti-CD28 antibody),
Ticilimumab (alias:Tremelimumab (anti-CTLA-4 antibody), Tigatuzumab (2 antibody of anti-TRAIL-R), TNX-
650 (anti-il-13 antibodies), Torr pearl monoclonal antibody (alias Atlizumab, Actemra, RoActemra, (anti-IL-6 receptor antibodies),
Toralizumab (anti-CD154 (CD40L) antibody), tositumomab (anti-CD 20 antibodies), Herceptin (Trastuzumab, it is (anti-
HER2/neu protein antibodies), Tremelimumab (anti-CTLA-4 antibody), Tucotuzumab celmoleukin (anti-EpCAMs
Antibody), Tuvirumab (anti-hepatitis B virus antibody), Urtoxazumab (anti-Escherichia coli antibody), this excellent its monoclonal antibody is (not
Name:Stelara, anti-IL-12, IL-23 antibody), sharp former times monoclonal antibody (anti-AOC3 (VAP-1) antibody) is cut down, Vedolizumab is (anti-whole
Close 4 β of element α, 7 antibody), Veltuzumab (anti-CD 20 antibodies), vepalimomab (anti-AOC3 (VAP-1) antibody, Visilizumab
(alias:Nuvion, anti-cd 3 antibodies), Vitaxin (anti-angiogenic integrin av b3 antibody), Volociximab (anti-Integrin α_5 β
1), Votumumab (alias:HumaSPECT, antitumor antigens CTAA16.88 antibody), prick appropriate wooden monoclonal antibody (alias:HUMAX-
EGFR, (anti-egfr antibodies), Zanolimumab (alias:HUMAX-CD4, anti-CD 4 antibodies), Ziralimumab (anti-CD147
(fundamental immunity globulin) antibody), Zolimomab Aritox (anti-CD5 antibody), EtanerceptAh method's SaiteOrenciaLi Naxipu (ARCALYST), 14F7 [anti-IRP-2 (iron from
Sub- regulatory protein 2) antibody], (anti-GD2 ganglioside antibodies, treat melanoma and solid tumor, Nat.cancer to 14G2a
Inst.), J591 (anti-PSMA antibody, treats prostate cancer, Weir Cornell medical college), 225.28S [anti-HMW-MAA (high scores
Son amount melanic related antigen) antibody, Suo Lin Radiofarmaci SRL (Milan, ITA) treatments melanoma], COL-1
(anti-CEACAM3 antibody, CGM1, Nat.cancer inst..The U.S. is used to treat colorectal cancer and stomach cancer), CYT-356 (Treat prostate cancer), HNK20 (OraVax companies, for treating Respiratory Syncytial Virus(RSV)), ImmuRAIT (come
Non-Hodgkin lymphoma is treated from Immunomedics), Lym-1 (anti-HLA-DR10 antibody, BNP Paribas Peregrine medicine, for cancer),
[anti-TNF antibodies are (also known as by MAK-195F:Tumor necrosis factor;TNFA, tumor necrosis factor-alpha;TNFSF2), Alpert/Nore,
For treating septicemia toxic shock], MEDI-500 [alias:T10B9, anti-cd 3 antibodies, TR α β (φt cell receptor α/β) are multiple
Compound, MedImmune companies are used to treat graft versus host disease(GVH disease)], RING SCAN [anti-TAG72 (tumor-associated glycoproteins 72
Antibody), Neoprobe groups, for treating breast cancer, colon cancer and the carcinoma of the rectum.((epithelium is thin for anti-EpCAM antibody by Avicidin
Intercellular adhesion molecule), anti-TACSTD1 antibody (tumour correlation Ca2+ oscillations tranducin 11), anti-GA733-2 (stomach and intestine tumor GAP-associated protein GAP 2),
Anti- EGP-2 antibody (Glycoproteins in Epithelial 2);Anti- KSA antibody;KS1/4 antigens;M4S;Tumour antigen 17-1A;CD326, comes from
NeoRx companies are used to treat colon cancer, oophoroma, prostate cancer and non-Hodgkin lymphoma;LymphoCide
(IMMUNOMEDICS companies, NJ), (Techniclone is public by smart ID10 (Protein Design Labs), Oncolym
Department, California), Allomune (Bio-Transplant, CA), anti-VEGF antibody (Genentech companies, CA);
CEAcide (IMMUNO-MEDICS companies, NJ), IMC-1C11 (ImClone, NJ) and Cetuximab (ImClone companies, U.S.
State New Jersey).
It is other that there are anti-following antigens (but being not limited only to this) with the antibody of ligand binding, this antibody:Aminopeptidase N
(CD13), Annexin A1, B7-H3 (CD276, various cancers), CA125, CA15-3 (cancer), CA19-9 (cancer), L6 (cancer),
Lewis Y (cancer), Lewis X (cancer), alpha-fetoprotein (cancer), CA242, P-ALP (cancer), prostate specific resists
Former (prostate cancer), prostatic acid phosphatase (prostate), epidermal growth factor (cancer), CD2 (Hodgkin's disease, non-Hodgkin's
The lymthoma of lymthoma, Huppert's disease), the ε of CD3 (t cell lymphoma, lung cancer, breast cancer, stomach cancer, oophoroma, itself
Immunity disease, malignant ascite), CD19 (B cell malignant tumour), CD20 (non-Hodgkin lymphoma), CD22 (leukaemia, leaching
Bar knurl, Huppert's disease, systemic loupus erythematosus), CD30 (Hodgkin lymphoma), CD33 (leukaemia, autoimmunity disease
Disease), CD38 (Huppert's disease), CD40 (lymthoma, Huppert's disease, leukaemia), CD51 (metastatic melanoma, meat
Knurl), CD52 (leukaemia), CD56 (Small Cell Lung Cancer cancer, oophoroma, Merkel cell cancers, and liquid tumors, multiple bone
Myeloma), CD66e (cancer), CD70 (metastatic renal cell cancer and non-Hodgkin lymphoma), CD74 (Huppert's disease),
CD80 (lymthoma), CD98 (cancer), mucoprotein (cancer), CD221 (solid tumor), CD227 (breast cancer, oophoroma), CD262
(non-small cell lung cancer and other cancers), CD309 (oophoroma), CD326 (solid tumor), CEACAM3 (colorectal cancer, stomach cancer),
CEACAM5 (carcinomebryonic antigens;CEA, CD66e) (breast cancer, colorectal cancer and lung cancer), (epidermis is given birth to by DLL4 (Δ shape -4), EGFR
Growth factor receptor body, various cancers), CTLA4 (melanoma), CXCR4 (CD184, ferroheme tumour, entity tumor), interior sugar sweet
Albumen (CD105, solid tumor), EPCAM (epithelial cell adhesion molecule, carcinoma of urinary bladder, head, neck, colon, the leaching of prostate non-Hodgkin's
Bar knurl, and oophoroma), ERBB2 (epidermal growth factor acceptor 2s;Lung cancer, breast cancer, prostate cancer), FCGR1 (autoimmune
Disease), FOLR (folacin receptor, oophoroma), GD2 gangliosides (cancer), a kind of G-28 (cell surface antigens
Glyvolipid, melanoma), idiotype GD3 (cancer), heat shock protein (cancer), HER1 (lung, stomach cancer), HER2 (mammary gland
Cancer, lung cancer and oophoroma), HLA-DR10 (NHL), HLA-DRB (non-Hodgkin lymphoma, B cell leukemia), human chorionic promote
Gonadal hormone (cancer), IGF1R (type-1 insulin like growth factor acceptor, solid tumor, hematologic cancers), IL-2 acceptor (interleukins
2 acceptors, T- chronic myeloid leukemias and lymthoma), IL-6R (interleukin-6 receptor, Huppert's disease, rheumatoid joint
Inflammation, Castleman disease, IL6 dependent tumors), integrin (5 β 1 of α v β 3, α, alpha 6 beta 4,5 cell of α ll β 3, α 5 β 5, α v β attachment because
Son, to various cancers), MAGE-1 (cancer), MAGE-2 (cancer), MAGE-3 (cancer), MAGE 4 (cancer), anti-rotation Human Placental Ferritin Receptor
(cancer), P97 (melanoma), MS4A1 (4 subfamily A member 1 of membrane-spanning domain, non-Hodgkin's B cell lymphoma, leukaemia), MUC1 or
MUC1-KLH (breast cancer, oophoroma, cervix cancer, bronchus and gastrointestinal cancer), MUC16 (CA125) (oophoroma), CEA
(large intestine), GP100 (melanoma), MART1 (melanoma) MPG (melanoma), MS4A1 (4 albumin A of membrane-spanning domain, cellule
Lung cancer, non-Hodgkin lymphoma), kernel, neural oncoprotein (cancer), P21 (cancer), resists (NeuGc ALPHA2-3Gal, mammary gland
Cancer, the cancer of melanoma), PLAP sample testis alkaline phosphatase (oophoroma, carcinoma of testis), PSMA (tumor of prostate), PSA
(prostate), in ROBO4, TAG 72 (tumor-associated glycoprotein 72, leukaemia, stomach cancer, colorectal cancer, oophoroma), T cell
Transmembrane protein (cancer), Tie (CD202b), TNFRSF10B (A member of the TNF receptor family 10B, cancer),
TNFRSF13B (A member of the TNF receptor family 13B, Huppert's disease, non-Hodgkin lymphoma, and other
Cancer, rheumatoid arthritis and systemic loupus erythematosus), TPBG (trophoderm glycoprotein, clear-cell carcinoma), TRAIL-R1 are (swollen
Knurl necrosis apoptosis induction ligand acceptor 1, lymthoma, non-Hodgkin lymphoma, colorectal cancer, lung cancer), VCAM-1 (CD106, black
Plain knurl), vascular endothelial growth factor, vascular endothelial growth factor-A, VEGF-2 (CD309) (various cancers).Known by antibody
Other some other tumor associated antigen has checked (Gerber etc., mAbs 1:3,247-253 (2009);Novellino etc.
People, Cancer Immunol Immunother.54 (3), 187-207 (2005) Franke et al., Cancer
Biother.Radiopharm.2000,15,459-76).
Cell binding agent, preferred antibody, can be can antitumor cell, virus infection cell, microorganism sense
The cell of dye, the cell of parasitic infection, autoimmunity cell, the cell of activation, bone marrow cell, the T cell of activation, B cell,
Or melanocyte.More specifically, cell binding agent can be can resist any one of following antigen or acceptor any
Reagent/molecule:CD3,CD4,CD5,CD6,CD7,CD8,CD9,CD10,CD11a,CD11b,CD11c,CD12w,CD14,CD15,
CD16,CDw17,CD18,CD19,CD20,CD21,CD22,CD23,CD24,CD25,CD26,CD27,CD28,CD29,CD30,
CD31,CD32,CD33,CD34,CD35,CD36,CD37,CD38,CD39,CD40,CD41,CD42,CD43,CD44,CD45,
CD46,CD47,CD48,CD49b,CD49c,CD51,CD52,CD53,CD54,CD55,CD56,CD58,CD59,CD61,
CD62E,CD62L,CD62P,CD63,CD66,CD68,CD69,CD70,CD72,CD74,CD79,CD79a,CD79b,CD80,
CD81,CD82,CD83,CD86,CD87,CD88,CD89,CD90,CD91,CD95,CD96,CD98,CD100,CD103,
CD105,CD106,CD109,CD117,CD120,CD125,CD126,CD127,CD133,CD134,CD135,CD138,
CD141,CD142,CD143,CD144,CD147,CD151,CD147,CD152,CD154,CD156,CD158,CD163,
CD166,.CD168,CD174,CD180,CD184,CDw186,CD194,CD195,CD200,CD200a,CD200b,CD209,
CD221,CD227,CD235a,CD240,CD262,CD271,CD274,CD276(B7-H3),CD303,CD304,CD309,
CD326,4-1BB,5AC,5T4(Trophoblast glycoprote-in,TPBG,5T4,Wnt-Activated
Inhibitory Factor 1or WAIF1),
Cell binding agent, preferred antibody, can be can antitumor cell, virus infection cell, microorganism sense
The cell of dye, the cell of parasitic infection, autoimmunity cell, the cell of activation, bone marrow cell, the T cell of activation, B cell,
Or melanocyte.More specifically, cell binding agent can be can resist any one of following antigen or acceptor any
Reagent/molecule:CD3,CD4,CD5,CD6,CD7,CD8,CD9,CD10,CD11a,CD11b,CD11c,CD12w,CD14,CD15,
CD16,CDw17,CD18,CD19,CD20,CD21,CD22,CD23,CD24,CD25,CD26,CD27,CD28,CD29,CD30,
CD31,CD32,CD33,CD34,CD35,CD36,CD37,CD38,CD39,CD40,CD41,CD42,CD43,CD44,CD45,
CD46,CD47,CD48,CD49b,CD49c,CD51,CD52,CD53,CD54,CD55,CD56,CD58,CD59,CD61,
CD62E,CD62L,CD62P,CD63,CD66,CD68,CD69,CD70,CD72,CD74,CD79,CD79a,CD79b,CD80,
CD81,CD82,CD83,CD86,CD87,CD88,CD89,CD90,CD91,CD95,CD96,CD98,CD100,CD103,
CD105,CD106,CD109,CD117,CD120,CD125,CD126,CD127,CD133,CD134,CD135,CD138,
CD141,CD142,CD143,CD144,CD147,CD151,CD147,CD152,CD154,CD156,CD158,CD163,
CD166,.CD168,CD174,CD180,CD184,CDw186,CD194,CD195,CD200,CD200a,CD200b,CD209,
CD221,CD227,CD235a,CD240,CD262,CD271,CD274,CD276(B7-H3),CD303,CD304,CD309,
CD326,4-1BB, 5AC, 5T4 (trophocyte's glycoprotein, TPBG, 5T4, Wnt activation inhibiting factors 1 or WAIF1), gland cancer resists
Original, AGS-5, AGS-22M6, activin receptor sample kinases 1, AFP, AKAP-4, ALK, α integrins, α v β 6, aminopeptidase N, forms sediment
Powdered protein β, androgen receptor, angiopoietin 2, angiogenesis hormone 3, Annexin A1, anthrax toxin protective antigens,
Anti-rotation Human Placental Ferritin Receptor AOC3 (VAP-1), B7-H3, bacillus anthracis anthrax-bacilus, cell activating agent), B- lymphoma cells,
Bcr-abl, bombesin, BORIS, C5, C242 antigens, CA125 (Carbohydrate Antigens 125, MUC16), CA-IX (or CAIX,
Carbonic anhydrase 9), CALLA, CanAg, familial lupus family IL31, carbonic anhydrase IX, Cardi-ac myosin, CCL11
(CC motifs chemotactic factor (CF) 11), CCR4 (4 type of CC-chemokine receptor, CD194), CCR5, CD3E (ε), CEA (carcinomebryonic antigen),
CEACAM3, CAM5 (carcinomebryonic antigen), CFD (factor D), Ch4D5, cholecystokinin 2 (CCK2R), CLDN18 (claudin-3s
It is white 18), (colony stimulating factor 2, granulocyte is huge by coagulation factor A, CRIPTO, FCSF1R (colony-stimulating factor 1 acceptor, CD115)
Phagocyte colony stimulating factor (GM-CSF)), CTLA4 (cytotoxic T lymphocyte GAP-associated protein GAP 4), CTAA16.88 tumours resist
Original, CXCR4 (CD184), C-X-C Chemokine receptor4 types, ring-type ADP ribose hydrolases, cell periodic protein B 1, CYP1B1,
Cytomegalovirus, cytomegalovirus Glycoprotein B, dabigatran, DLL4 (δ samples ligand 4), DPP4 (dipeptidyl peptidase 4), DR5 are (dead
Die acceptor 5) type of colon bacillus shiga toxin -1, the type of colon bacillus shiga toxin -2, ED-B, EGFL7 (EGF spline structures domain albumen
7), EGFR, EGFRII, EGFRvIII, Endoglin (CD105), Endothelin B receptor, endotoxin, (epithelial cell glues EpCAM
Attached molecule), EphA2, Episialin, ERBB2 (epidermal growth factor acceptor 2), (TMPRSS2ETS merges base by ERBB3, ERG
Cause), Escherichia coli, ETV6-AML, FAP (fibroblast activation protein alpha), FCGR1, α-fetoprotein, fibronectin additional knot
Structure domain-B, FOLR (folacin receptor), folacin receptor α, folic acid hydrolase, Fos related antigen 1.F respiratory protein syncytial viruses,
Fz receptor, fucosido GM1, GD2 gangliosides, G-28 (cell surface antigen glyvolipid), GD3 are unique
Type, GloboH, glypican-3, NeuGc ALPHA2-3Gal GM3, GMCSF receptor alpha chain, Growth differentiation factor 8,
GP100, GPNMB (transmembrane glycoprotein NMB), GUCY2C (guanylate cyclase 2C, guanosine cyclic mono-phosphate-C), enteron aisle guanylic acid
Cyclase, guanylate cyclase-C acceptors, Thermostable α-amylase acceptor (hSTAR)), heat shock protein, hemagglutinin, hepatitis B
Surface antigen, hepatitis type B virus, HER1 (human epidermal growth factor acceptor 1), HER2, HER2/neu, HER3 (ERBB-3),
IgG4, HGF/SF (hepatocyte growth factor/dispersion factor), HHGFR, HIV-1, histone complexes, HLA-DR (human leukocytes
Antigen) HLA-DRB, HMW-MAA, human chorionic gonadotrophin, HNGF, people's dispersion factor receptor kinase, HPV E6/E7,
Hsp90, hTERT, ICAM-1 (Intercellular Adhesion Molecule 1), idiotype, IGF1R (IGF-1, type-1 insulin like growth factor
Acceptor), IGHE, IFN-γ, influenza hemagglutinin, IgE, IgE Fc areas, IGHE, IL-1, IL-2 acceptors (interleukin 2 by
Body), IL-4, IL-5, IL-6, IL-6R (interleukin-6 receptor), IL-9, IL-10, IL-12, IL-13, IL-17, IL-
17A, IL-20, IL-22, IL-23, IL31RA, ILGF2 (insulin-like growth factor 2), integrin (α 4, αIIbβ3,αvβ3,
α4β7, 5 β 1 of α, alpha 6 beta 4, α 7 β 7, α ll β 3, α 5 β 5, α v β 5), interferon gamma inducible protein, ITGA2, ITGB2, KIR2D, LCK,
Le, Legumain, Lewis-Y antigen, LFA-1 (Lymphatic diseases, CD11a), LHRH, LINGO-1, fat born of the same parents
Teichaic acid matter, LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1, MAGE-3, MAGE A1, MAGE A3, MAGE 4,
MART1, MCP-1, MIF (macrophage migration inhibitory factor or glycosylation inhibiting factor (GIF)), MS4A1 (4 domains of cross-film
Subfamily A member 1), MSLN (mesothelin), MUC1 (mucin 1, cell surface association (MUC1) or Polymorphic epithelial mucin
(PEM)), MUC1-KLH, MUC16 (CA125), MCP1 (MCP 1), Mela-nA/MART1, ML-IAP,
MPG, MS4A1 (cross-film 4- domains subfamily A), MYCN, myelin associated glucoprotein, myostatin, NA17, NARP-
1, NCA-90 (G-Ag), Nectin-4 (ASG-22M E), NGF, neural apoptosis regulatory protein enzyme 1, NOGO-A, Notch
Acceptor, paranuclein, Neu oncoproteins, NY-BR-1, NY-ESO-1, OX-40, OxLDL (OxLDL ELISA), OY-
TES1,P21,p53nonmutant,P97,Page4,PAP,Paratope of anti-(N-glycolylneuraminic
Acid), PAX3, PAX5, PCSK9, PDCD1 (PD-1, apoptosis albumen 1, CD279), PDGF-R α, PY1, PY1,
P13, P53, unmanifest type P97, PAP, Paratope, anti-PAA3, PAX5, PCSK9, PDCD1 (α types platelet derived growth because
Sub- acceptor), PDGFR- β, PDL-1, PLAC1, PLAP sample testis alkaline phosphatases, platelet derived growth factor receptor β, phosphoric acid
Sodium cotransports albumen, PMEL17, poly sialic acid, protease 3 (PR1), prostate cancer, PS (phosphatidylserine), prostate cancer
Cell, pseudomonas aeruginosa, PSMA, PSA, PSCA, rabies virus glucoprotein, RHD (Rh polypeptides 1 (RhPI), CD240) are permanent
The river monkey factor, RANKL, RhoC, Ras mutant, RGS5, ROBO4, Respiratory Syncytial Virus(RSV), RON, sarcoma translocation breakpoint,
SART3, hardened proteins, SLAMF7 (SLAM family members 7) select albumen P, SDC1 (Syndecan1), sLe (a), and growth is adjusted
PROTEIN C is saved, SIP (sphingosine-1-phosphate), growth hormone release inhibiting hormone, Human sperm protein 17, SSX2, STEAP1 are (in six cross-films of prostate 1
Skin antigen), STEAP2, STn, TAG-72 (tumor-associated glycoprotein 72), survivin, φt cell receptor, T cell transmembrane protein,
TEM1 (tumor endothelial marker 1), TENB2, Tenascin C (TN-C), TGF- α, TGF-β (transforming growth factor β), TGF-β 1,
TGF-β 2 (transforming grouth factor beta 2), Tie2 (CD202b), Tie2, TIM-1 (CDX-014), Tn, TNF, TNF-α, TNFRSF8,
TNFRSF10B (A member of the TNF receptor family 10B), TNFRSF13B (A member of the TNF receptor family
13B), TPBG (trophoderm glycoprotein), TRAIL-R1 (neoplasm necrosis apoptosis induction ligand acceptor 1), TRAILR2 (it is dead by
Body 5 (DR5)), tumour correlation Ca2+ oscillations transductant 2, the tumour-specific glycosylation of MUC1, tweak receptor, TYRP1 (glycoprotein
75), TRP-2, tyrosinase, VCAM-1 (CD106), VEGF, VEGF-A, VEGF-2 (CD309), VEGFR-1, VEGFR2 or ripple
Shape albumen, the cell of WT1, XAGE1 or any expression of insulin growth factor receptors, or any EGF-R ELISA epidermis
The cell of growth factor receptors.
In another specific embodiment, cellular binding partners-medicine via the hydrophilic chain junctor of the present invention is even
Join the targeted therapy that thing is used for cancer.Target on cancer includes but not limited to adrenocortical carcinoma, cancer of anus, carcinoma of urinary bladder, brain tumor
(adult, brain stem glioma, childhood, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, medulloblastoma,
Primitive neuroectodermal and Pinealoma on curtain, optic nerve glioma), breast cancer, carcinoid tumor, gastrointestinal cancer, unknown original
Hair property cancer, cervical carcinoma, colon cancer, carcinoma of endometrium, the cancer of the esophagus, cholangiocarcinoma, You Wenshi family tumors (PNET), cranium are external
Cell colonization tumour, cancer eye disease, intraocular melanoma, gallbladder cancer, stomach cancer (stomach), gonioma, outside embryo, gestational trophoblast swells
Knurl, incidence cancer, hypopharyngeal cancer, islet-cell carcinoma, kidney (clear-cell carcinoma), laryngocarcinoma, leukaemia (acute lymphocytic, it is acute
It is myeloide, chronic lymphocytic, chronic granulocytic, hair cell), lip and carcinoma of mouth, liver cancer, lung cancer (non-small cell, it is small thin
Born of the same parents), lymthoma (AIDS is related, central nervous system, cutaneous T-cell, Hodgkin's disease, non-Hodgkin lymphoma), malignant mesothelioma,
Melanoma, merkel's cells cancer, invisible primary, Huppert's disease, myeloproliferative disorder, nasopharyngeal carcinoma, neuroblast
Knurl, carcinoma of mouth, oropharyngeal cancer, osteosarcoma, oophoroma (epithelial tumor, gonioma, low malignant potential tumour), cancer of pancreas
(exocrine cell knurl, islet-cell carcinoma), nasal sinus cancer, nasal sinus cancer, parathyroid carcinoma, carcinoma of penis, pheochromocytoma cancer, hypophysis
Cancer, plasmacytoma, prostate cancer rhabdomyosarcoma, the carcinoma of the rectum, clear-cell carcinoma (kidney), renal plevis and ureter (migratory cell)
Cancer, salivary-gland carcinoma, Sezary syndrome, cutaneum carcinoma, cutaneum carcinoma (skin T cell lymphoma, Kaposi sarcoma, melanoma),
Carcinoma of small intestine, soft tissue sarcoma, stomach cancer, carcinoma of testis, thymoma (pernicious), thyroid cancer, carcinoma of urethra, uterine cancer (sarcoma), does not seek
Normal childhood cancer, carcinoma of vagina, carcinoma of vulva, the nephroblastoma.
In another specific embodiment, the present invention is passed through using cell-binding molecules-drug conjugates of hydrophilic chain junctor
Its component and method can be used for treating or preventing autoimmune disease.Autoimmune disease includes, but not limited to gastric anacidity
Autoimmune chronic active hepatitis, acute diseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, Addison's disease, third
Kind globulinemia, alopecia areata, amyotrophic lateral sclerosis, ankylosing spondylitis, anti-GBM/renal tubular basement membrane
Ephritis, antiphospholipid syndrome, anti-synzyme syndrome, arthritis, atopy allergy, allergic dermatitis, autoimmune is again
Raw aplastic anemia, autoimmune cardiomyopathy, autoimmune hemolytic anemia, oneself immunity hepatitis, autoimmune
Inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral nervous disease, autoimmune pancreas
The scorching more endocrine disease I of autoimmunity, II, type III, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura,
Autoimmune uveitis, Balo disease/Balo concentric sclerosis, bechet's syndrome, Berger diseases, Bickerstaff brains
Brain stem encephalitis, Blau syndromes, big bud class day bud sore, castleman disease, American trypanosomiasis, chronic fatigue immune dysfunction
Syndrome, the multiple neuropathy of chronic inflammation demyelinating, chronic recurrent multifocal osteomyelitis, chronic Lyme disease are chronic
Obstructive disease of lung, allergic granulomatous angiitis, cicatricial pemphigoid, abdominal disease, Cogan's syndrome, condensation
Collection element disease, complement C2 deficiency diseases, cranial arteritis, CREST syndrome, clone disease (a kind of idiopathic inflammatory bowel diseases), Ke
Xing Shi diseases, skin leukocytoclastic vasculitis, malignant atrophic papulosis, adiposis dolorosa, dermatitis herpetiformis, dermatomyositis, 1
Patients with type Ⅰ DM, diffusivity skin chorionitis, postmyocardial infarction syndrome, lupus erythematosus discoides, eczema, endometriosis,
Juvenile idiopathic arthritis, eosinophilic fasciitis, eosinophilic fasciitis, erythema nodosum, idiopathic Combination are cold
Globulinemia, Evan's syndome, gradual ossificans structure of fibrous tissue is bad, fibromyalgia, fibromyositis, fibroid
Pulmonary alveolitis, gastritis, stomach and intestine pemphigoid, giant cell arteritis, glomerulonephritis, Goodpasture's syndrome, Graves
Disease, guillain-Barre ramitis, this encephalitis of bridge, struma lymphomatosa, hemolytic anemia, anaphylactoid purpura is more, the gestational period
Bleb, suppurative hidradenitis, Hughes's syndrome (antiphospholipid antibody syndrome), hypogammaglobulinemia, idiopathic inflammatory takes off marrow
Sheath disease, idiopathic pulmonary fibrosis, Idiopathic Thrombocytopenic Purpura (autoimmune thrombocytopenic purpura), IgA
Nephrosis (Berger diseases), inclusion body myositis, inflammatory Demyelination, interstitial cystitis, irritable bowel syndrome, childhood special hair
Property arthritis, infantile rheumatoid arthritis, mucocutaneous lymph node syndrome, Lambert myasthenic syndrome, leucocyte
Fissility vasculitis, lichen planus, lichen sclerosus, wire IgA diseases (LAD), amyotrophic lateral sclerosis, lupoid acne liver
Inflammation, lupus erythematosus, Ma Jide syndromes, Meniere's syndrome, microscopic polyangitis, Miller fisher's syndrome,
Mixed connective tissue disease, morphoea, Mu breathe out Er Shi diseases, Wells syndrome, Huppert's disease, multiple sclerosis, weight
Disease myasthenia, myositis, narcolepsy, neuromyelitis optica (devic's disease), neuromyotonia, eye cicatricial class day blister
Sore, opsoclonus-myoclonic syndrome, Ao Deshi thyroiditis, palindromic rheumatism, panda syndrome (merge streptococcal infection
Children's autoimmunity neuropsychiatric abnormalities), paraneoplastic cerebellar degeneration, paraoxysmal nocturnal hemoglobinuria, progressive
Hemifacial atrophy, two Cotard of Ba-spy, pars planitis, pemphigus, pemphigus vulgaris, pernicious anaemia, vein week
Enclose inflammation, POEMS syndromes, nodular polyarteritis, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, original
Hair property sclerosing cholangitis, progressive inflammatory neuropathies become, and psoriasis, psoriatic arthritis, gangraenosum purulence skin, pure red cell is again
Raw aplastic anemia, Ross are write from memory Sen Shi encephalitis, Raynaud's disease, relapsing polychondritis, Reiter syndrome, restless leg syndrome,
Retroperitoneal fibrosis, rheumatoid arthritis, rheumatoid fever, sarcoidosis, schizophrenia, Schmidt syndrome, Schnitzler
Syndrome, sclerotitis, chorionitis, Sjogren syndrome, spondyloarthropathy, glues blood syndrome, Still disease, stiff man syndrome, Asia
Acute bacterial endocarditis, Susac Cotards, acute febrile neutrophilia skin disease, sydenham chorea, associability eye
Inflammation, high iS-One arteritis, temporal arteritis (giant cell arteritis), Tolosa-Hunt syndrome, transverse myelitis are exedens
Colitis (a kind of idiopathic inflammatory intestinal disease), undifferentiated connective tissue disease, undeveloped ovules, vasculitis, in vain
Purplish or white patches on the skin wind, Wei Genashi granulomatosis, Wilson's syndrome, Wiskott-Aldrich syndrome.
In another embodiment, exempted from by what the hydrophilic chain junctor of the present invention linked for treating or preventing itself
The cell-binding molecules of epidemic disease include, but are not limited to:Elastoresistance protein antibodies;The anti-epithelial cell antibody of Abys;Anti- basilar memebrane
IV collagen type antibody;Antinuclear antibodies;Anti-dsDNA antibody;Anti-ssDNA antibody, anticardiolipin antibodies IgM, IgG;
Anti- celiac antibody;Anti-phospholipid antibody IgK, IgG;Anti- nucleoglucoprotein antibody;Anti-mitochondrial antibody;Thyroid antibody;Microsome
Antibody, T- cell antibodies;Thyroglobulin antibody, the anti-antibody of chorionitis -70 (anti-SCL-70);The anti-Jo antibody of people;Anti- system
System property patients with SLE autoantibody;Resist drying syndrome antibody (Anti-La/SSB);Anti- systemic loupus erythematosus antibody;
Anti-parietal cell anti-body;Histonic antibody;Anti ribonucleoprotein antibody (anti-RNP);Neutrophil leucocyte cytoplasmic antibody (C-
ANCA);Anti- Antineutrophil antibody (P-ANCA) around nucleus;Anti centromere antibody;Anti- core fibrin antibody, Yi Jikang
GBM Antibody (GBM) antibody, Barrier pressure;Anti desmoglein 3 antibody (anti-Desmogein
3);Anti-human P62 antibody;Anti-human sp100 antibody;Resist mitochondria M2 antibody;Rheumatoid factor antibodies;Anti- saltant type citrulling waveform
Protein antibodies (anti-MCV);Anti- topoisomerase enzyme antibody;Anti- neutrophil leucocyte endochylema (CANCA) antibody.
In certain preferred aspects, the binding molecule for being conjugated coupling is used in the present invention, can be with autoimmunity
Property disease relevant activated lymphocyte expression acceptor or receptor complex combine.Including immunoglobulin gene superfamily into
Member (such as CD2, CD3, CD4, CD8, CD19, CD20, CD22, CD28, CD30, CD37, CD38, CD56, CD70, CD79, CD90,
CD125, CD152/CTLA-4, PD-1, PDL-1, or ICOS), TNF receptor superfamilies member (such as CD27, CD40, CD95/Fas,
CD134/OX40, CD137/4-1BB, INF-R1, TNFR-2, RANK, TACI, BCMA, osteoprotegerin, Apo2/TRAIL-R1,
TRAIL-R2, TRAIL-R3, TRAIL-R4, APO-3), integrin, cytokine receptor, chemokine receptors, Main Tissues
Compatible protein, agglutinin (c-type, S types or I types) or complement regulatory proteins.
In another particular embodiment, there is the useful combination of immunologic opsonin to viral or bacterial antigen
It is humanization or human monoclonal antibody.Terms used herein " viral antigen " includes, but are not limited to:Any can induce is exempted from
The viral peptide fragment of epidemic disease reaction, polypeptide protein is (for example, HIVgp120, HIV nef, RSV F glycoprotein, influenza virus neuraminidase
Enzyme, influenza virus hemagglutinin, human T-lymphocyte virus infection regulatory factor tax, herpes virus glycoprotein (for example, gB,
GC, gD and gE) and hepatitis B surface antibody).Term " bacterial antigen " used herein includes, but are not limited to:Any energy
The microorganism peptide fragment of immune response is induced, polypeptide protein, carbohydrate, polysaccharide, lipid molecular is (for example, bacterium, fungi, pathogenic original
Lively thing, yeast polypeptides include, for example, lipopolysaccharides and capsular polysaccharide 5/8).It is viral or bacterial infection available for treating
Antibody includes, but are not limited to:Palivizumab, a kind of preventing respiratory syncytial virus list in the people source for being used to treat rsv infection
Clonal antibody;PRO542, a kind of CD4 fusion antibodies for being used to treat HIV infection;Ostavir, one kind treat hepatitis B people source
Property antibody;PROTVIR, one kind are used to treat cytomegalovirus Humanized immunoglobulin hypotype I antibody, also have anti-grease polysaccharide
(anti-LPS) antibody.
It can be used for treating infectiousness by cell-binding molecules-drug conjugates of the preparation of the hydrophilic connector of the present invention
Disease.These infectious diseases include, but are not limited to:Acinetobacter, lumpy jawl clams, lethargus (African typanosomiasis nagana), Chinese mugwort
Grow sick (Immune Deficiency Syndrome), amcbiasis, Anaplasmosis, anthrax, arcanobacterium haemolyticum infection, Argentina
Hemorrhagic fever, roundworm disease, aspergillosis, astrovirus infection, babesiasis, Bacillus cereus infection, bacterial pneumonia, bacterium
Vaginosis, bacteroides infection, balantidiasis, Baily ascarid nematode infections, BK virus infection, black piedra, people's bud capsule are former
Insect infection, blastomycete, Bolivian hemorrhagic fever, borrelia infection, botulismus (and baby's botulismus), Brazilian hemorrhagic
Heat, brucellosis, Bai Huoerde bacillus infections, Bu Luli ulcer, infection calicivirus (norovirus and Sapporo virus) are curved
Aspergillosis, monilial infection (candidiasis, thrush), cat scratch disease, cellulitis, Chaggs'disease (American trypanosomiasis) are soft
Chancre, varicella, Chlamydia, infection involving chlamydia pneumoniae, cholera, chromoblastomycosis, liver rot, Clestridium difficile sense
Dye, coccidioidomycosis, colorado tick fever, common cold (acute virus nasopharyngitis;Acute rhinitis), creutzfeldt-Jacob disease, Ke Li meter
Asia-Crimean-Congo Hemorrhagic Fever, cryptococcosis, Cryptosporidiosis, cutaneous larva migrans, Cyclospora infection, cysticercosis, giant cell disease
Poison infection, dengue fever, Dientamoeba disease, diphtheria, diphyllobothrium, dracunculiasis, Ebola hemorrhagic fever, echinococcosis, Ai Lixi
Body disease, enterobiasis (retrofection), enterococcal infection, enterovirus infection, epidemic typhus, erythema infectioum the (the 5th
Disease), exanthem subitum, fasciolopsiasis, fatal familial insomnia, filariasis, C.perfringens is caused to poison by food, non-to post
Raw amoeba infection, fusobacterium infections, emphysematous gangrene (clostridial myonecrosis), geotrichosis, lucky Stedman-Astrid Strauss synthesis
Sign, Giardiasis, glanders, ganthostomiasis, gonorrhoea, granuloma inguinale, the infection of A group of streptococcus, the infection of B group of streptococcus,
Acute Haemophilus influenzae infection, hand-foot-and-mouth disease (HFMD), Hantavirus pulmonary syndrome, helicobacter pylori infections, haemolytic uraemic are comprehensive
Simulator sickness, hemorrhagic fever with renal syndrome, hepatitis A, hepatitis B, hepatitis C, hepatitis D, Hepatitis E, herpe simplex,
Histoplasmosis, hookworm infection, people Bao Kan virus infection, people angstrom Wen Ehrlichia disease, Human granulocytic anaplasmosis, the mankind
Metapneumovirus infects, human monocyte's Ehrlichia disease, human papilloma virus infection, human parainfluenza viruses's infection, putamina
Taeniasis, epstein-Barr virus infectious mononucleosis (single), influenza, isosporiasis, Kawasaki disease,
Keratitis, Jin Shi Jin Shi bacillus infections, kuru, Lassa fever, legionellosis (legion member disease), Legionnella
Sick (Pontiac fever), leishmaniasis, leprosy, leptospirosis, listerellosis, Lyme disease (lime Borellia
Disease), Filariasis (elephant hide swell), lymphocytic choriomeningitis, malaria, marburg hemorrhagic fever, measles, glander-like disease
(Whitmore's disease), meningitis, meningococcosis, metagonimiasis, microsporidiosis, molluscum contagiosum, the popular cheek
Adenositis, typhus (matlazahuatl), Eaton agent pneumonia, madura diseasemadura foot, fly-blown, neonatal ophthalmia (neonate's eye
It is scorching), gram-Asia syndrome (vCJD, nvCJD), nocardiasis, onchocercosis (river blindness), paracoccidioidomycosis (South America
Blastomycosis), paragonimiasis, pasteurellosis, pediculosis capillitli (head louse), pediculosis corporis (body louse), pediculosis pubis (crab louse), pelvic infecton,
Pertussis, the plague, pneumococcal infection, pneumocystis carinii pneumonia, pneumonia, polio, general Salmonella infection, primary Ah meter
Bar meningoencephalitis, the more lesion leukoencephalopathies of progressive, psittacosis, Q heat, rabies, rat-bite fever, respiratory syncytial virus infection,
Rhinosporidiosis, rhinovirus infection, rickettsial infection, rickettsia, Rift Valley fever, exanthematic typhus of Sao Paulo, rotavirus sense
Dye, rubella, salmonellosis, SARS (SARS (Severe Acute Respiratory Syndrome)), scabies, snail fever, septicemia, dysentery (bacterium
Dysentery), herpes zoster (herpes zoster), smallpox (smallpox), sporotrichosis, staphylococcal food poisoning, staphy lococcus infection, line
Worm, syphilis, taeniasis, lockjaw (lockjaw), barber's itch, favus of the scalp, ringworm of the body, jock itch, the tinea manuum, tinea nigra, tinea pedis, onychomycosis,
Tinea versicolor, toxocarasis (larva migrans,ocular), toxocarasis (visceral larva migrans), toxoplasmosis, trichinosis, trichomonad
Disease, trichuriasis (whipworm infection), pulmonary tuberculosis, yatobyo, ureaplasma urealyticum infect, Venezuelan equine encephalitis, in committee
Auspicious pull-out blood-head, viral pneumonia, West Nile fever, white piedra (white piedra), false knot solani infection,
Ademilson bacterium disease, yellow fever, zygomycosis.
The cell-binding molecules being described in this patent are mainly inclined to as antibody.These antibody can be used to resist pathogenic
Bacterium.The pathogenic bacteria resisted include, but are not limited to:Acinetobacter bauamnnii, actinomyces Israeli, Ge Shi actinomyces and propionic acid propionic acid
Salt bacillus, trypanosoma bocagei, HIV (human immunodeficiency virus), Entamoeba histolytica, Anaplasma, bacillus anthracis, haemolysis are hidden
Secret bacillus, Junin virus, roundworm, aspergillus, astrovirus family, Babesia category, Bacillus cereus, more bacillus, class bar
Pseudomonas, balantidium Coli, Baylisascaris, BK virus, piedraia hortai, blastocystis hominis, Blastomyces dermatitidis are husky
Granulosis poison, Borrelia, clostridium botulinum, Sabia japonica, Brucella, usual Burkholderia cepacia and other primary gram of Hall
Moral bacillus specie, mycobacterium buruli, Caliciviridae family, campylobacter, is typically Candida albicans and other candida albicans
Belong to, Bartonella, A group of streptococcus and staphylococcus, schizotrypanum cruzi, haemophilus ducreyi, varicellazoster virus
(VZV), chlamydia trachomatis, chlamydia pneumoniae, comma bacillus, Fonsecaea pedrosoi, clonorchis sinensis, Clestridium difficile,
Posadasis spheriforme and Cocci-dioides posadasii, colorado tick fever virus, rhinovirus, coronavirus, prion gram
Ya Shi diseases, crimean-Congo hemorrhagic fever virus, Cryptococcus neoformans, Cryptosporidium, ancylostoma braziliense;multiple
Parasites, ring spore, taeniasis suis, cytomegalovirus, dengue fever virus (DEN-1, DEN-2, DEN-3 and DEN-4) entomophila
Virus, dientamoeba fragilis, Bacterium diphtheriae, Diphyllobothrium, Guinea worm, Ebola virus, Echinococcus, angstrom Garrick
Body category, pinworm, enterococcus spp, enterovirus genus, Rickettsia prowazeki, assays for parvovirus B 19, human herpes virus-6 and the mankind
Herpes virus 7 type, fasciolopsis buski, Fasciola hepatica and fasciola gigantica, FFI prions, Filarioidea superfamily, perfringens bar
Bacterium, Fusobacterium, C.perfringens, other fusobacteriums, geotrichum candidum, GSS prions, cercomonas intestinalis, glanders Bai Kehuo
That moral Salmonella, gnathostoma siamense and gnathostoma hispidum, NEISSERIA GONORRHOEAE, klebsiella granulomatis, micrococcus scarlatinae, agalasisa hammer
Bacterium, haemophilus influenzae, enterovirus, most of Coxsackie A disease poison and enteric virus71 type, Xin Nuowa viruses, H. pylori
Bacterium, Escherichia coli O 157:H7, bunyaviridae family, hepatitis A virus, hepatitis type B virus, Hepatitis C Virus, fourth
Hepatitis virus, Hepatitis E virus, herpes simplex virus type 1, herpes simplex virus type 2, histoplasma capsulatum, duodenum hook
Worm and Necator americanus, haemophilus influenzae, Human bocavirus, angstrom Wen's Ehrlichia, Anaplasmataceae, the inclined tuberculosis of the mankind
Poison, sand takes Ehrlichia, human papilloma virus, human parainfluenza viruses, Hymenolepis nana and diminution coating tapeworm, Epstein-Barr virus,
Orthomyxoviridae family, Isosporabelli, Jin Shi Jin Shi bacillus, Klebsiella Pneumoniae, Klebsiella ozaenas, kuru protein
Virus, Lassa virus, legionella pneumophilia, legionella pneumophilia, leishmania, Mycobacterium leprae and the crazy branches of Mi Man Xing Ma
Bacillus, Leptospira, Listeria, Bo Shi borrelia vincentiis and other Borrelias, bancroft's filaria and Wuchereria malayi,
Lymphocytic choriomeningitis virus (LCMV), Plasmodium, Marburg virus, measles virus, glander-like disease Burkholderia,
Neisseria meningitidis, Metagonimus Yokogawai, Microspora, mollascus contagiosum virus (MCV), mumps virus, Richettsia
Bacillus, mycoplasma pneumoniae, various bacteria (Madura mycomycete disease) and fungi (Madura mycomycete disease), parasitic Diptera fly
Maggot, chlamydia trachomatis and gonococcus, vCJD prions, nocardia asteroide and other Nocardia species, Onchocerca caecutiens,
Blastomyces brasiliensis, Paragonismus westermani and other Paragonimus, pasteurella, lice favus of the scalp, body louse, crab louse, pertussis
Bordetella, Yersinia pestis, streptococcus pneumonia, Pneumocystis carinii, poliovirus, prevotella,
Naegleria fowleri, JC viruses, chlamydia psittaci, Richettsia, rabies viruses, Streptobacillus moniliformis and rat-bite fever spiral shell
Revolve body, Respiratory Syncytial Virus(RSV), rhinosporidium seeberi, rhinovirus, rickettsiae, dermacetor akari, Rift valley fever disease
Poison, rickettsia rickettsii, rotavirus, rubella virus, Salmonella, SARS coronavirus, itch mite, blood fluke
Belong to, Shigella, varicellazoster virus, variola major or alastrim, Sporothrix schenckii, staphylococcus are golden yellow
Color staphylococcus, micrococcus scarlatinae, strongyloides intestinalis, microspironema pallidum, tapeworm category, clostridium tetani, trichophyton, break hair
Trichophyta, Trichophyton, acrothesium floccosum, Trichophyton rubrum and alpha fungus, exophiala werneckii, trichophyton, horse
Draw color Pseudomonas, Toxocara canis or belascaris cati, Infection of Toxoplasma Gondii, trichina, trichomonas vaginalis, whipworm, tubercle bacillus, native La Refu
Lang Xisi bacterium, Ureaplasma urealyticum, Venezuelan equine encephalitis virus, comma bacillus, guanarito virus, west nile virus, white
Trichosporon bacteria, yersinia pseudotuberculosis, yersinia enterocolitica, yellow fever virus, Mucoales (mucormycosis) and Entomophthorales
(worm mycosis), pseudomonas aeruginosa, campylobacter fetus (vibrios), Aeromonas hydrophila, Edwardsiella tarda, yersinia genus
Bacterium, shigella, shigella flexneri, Shigella sonnei, salmonella typhimurium, Treponema pertenue, Treponema
Carateneum, borrelia vincentii, Bo Shi borrelia vincentiis, Leptospira icterohemorrhagiae, Pneumocystis carinii, cloth Lu Shi
Bacterium, Brucella suis, Brucella, Mycoplasma, typhus pathogen, Rickettsia tsutsugumushi, coating
Pseudomonas;Disease fungus (aspergillus, Candida albicans, Histoplasma capsulatum);Protozoan (Entamoeba histolytica, vagina hair
Trichomonad, Trichomonas hominis, Tryoanosoma gambiense, Trypanosoma rhodesiense, Leishmania donovani, tropical Li Shiman are former
Worm, leishmania brasiliensis, pneumocystis carinii pneumonia, Plasmodium vivax, plasmodium falciparum, pernicious malaria) or worm (Japanese blood suction
Worm, Schistosoma mansoni, Schistosoma haematobium and hookworm).
Other include for treating a variety of viral diseases in the present invention as the antibody of cellular binding partners, but unlimited
In:The antigen that antibody acts on pathogenic virus includes example below but is not limited to:Variola virus, herpesviral, adenovirus, breast are more
Empty Viraceae, enterovirus section, Pironavirus section, Parvoviridae, reovirus, Retroviridae, influenza disease
Poison, parainfluenza virus, parotitis, measles, Respiratory Syncytial Virus(RSV), rubella, arboviruse, rhabdovirus, Arenaviridae,
Non-A/Non-B hepatitis viruses, rhinovirus, coronavirus, rotavirus section, tumour virus is [for example, hepatitis type B virus (liver
Cell cancer), human papilloma virus (cervical carcinoma, cancer of anus), kaposi sarcoma-associate herpesvirus (Kaposi's sarcoma), EB
Viral (nasopharyngeal carcinoma, Burkitt lymphoma, primary central nervous system lymphoma), MCPyV (Merkel cell cancer), SV40
(simian virus 40), Hepatitis C Virus (liver cancer), Human T-lymphotropic virus 1 (adult T-cell leukemia/lymph
Knurl), immune disorder causes virus:[such as human immunodeficiency virus (AIDS)];Central nervous system virus:[e.g., JCV (into
The more lesion leukoencephalopathies of row), MeV (subacute sclerosing panencephalitis), LCV (lymphocytic choriomeningitis), entomophila
Viral encephalitis, orthomyxoviridae family's (possible) (lethargic encephalitis), RV (rabies), vesicular stomatitis-India's Tobamovirus, rash
Viral meningitis, Ramsay Hunter syndrome II types;Polio (infantile paralysis, Postpolio syndrome),
Human T-lymphotropic virus 1 (tropical spastic paraplegia)];Cytomegalovirus (cytomegaloviral retinitis, HSV
(herpetic keratitis));Cardiovascular disease virus [such as Coxsackie virus (pericarditis, myocarditis)];Respiratory system/acute nasopharyngitis
Virus/viral pneumonia:[african lymphoma virus (herpesvirus 4 infection/infectious mononucleosis), it is big and small
Cellular virus;Sars coronavirus (Severe acute respiratory syndrome) orthomyxovirus:Influenza virus A/B/C (influenza/fowl stream
Sense), paramyxovirus:Human parainfluenza virus' (parainfluenza), Respiratory Syncytial Virus(RSV) (human airway syncytial virus), tuberculosis
Poison];Digestive system virus [MUV (parotitis), cytomegalovirus (cytomegalovirus esophagitis);Adenovirus (adenovirus sense
Dye);Rotavirus, norovirus, astrovirus, coronavirus;HBV (hepatitis B), Coxsackie virus, hepatitis A (first
Hepatovirus), HCV (Hepatitis C Virus), HDV (Hepatitis D virus), HEV (Hepatitis E virus), HGV (hepatitis G disease
Poison)];The virus [e.g., BK virus, MUV (parotitis)] of urogenital system.
According to further object, pharmaceutically acceptable carrier is included by the conjugated body of the hydrophilic chain link of the present invention
Component is used for treating cancer or autoimmune disease jointly.Treating cancer and the method for autoimmune disease are included in vitro, in vivo
Or in vitro therapy.Ex vivo application example, including drug-treated cultured cell in vitro, are killed except no expression target antigen
Cell beyond all cells;Or kill the cell for expressing undesired antigen.Treatment method as in vitro therapy
One example:Candidate stem cell is handled in vitro, kills defeated time former patient's body after diseased or malignant cell.For example, clinically
First pass through the tumour cell in indirect interior therapeutic removing marrow or lymphocyte and then defeated time former patient comes treating cancer and oneself
Body immunological diseases, or T cell in marrow and other lymphocytes are removed before transplantation to prevent to the immune short of money of graft
Anti-reflective should.Implementation is as follows:Bone marrow cell is obtained from patient or other individuals, is then adding containing for present invention conjugation medicine
37 DEG C of cultures, drug concentration scope be 1pM to 0.1mM in blood serum medium, incubation time be 30 minutes or so to 48 it is small when a left side
It is right.The specific concentration of medicine and incubation time are determined by veteran clinician.After culture, bone marrow cell, which is used, contains serum
After culture medium washing, according to known methods by being injected intravenously in defeated the Huis' body.If patient is obtaining bone marrow cell and feedback
Before processing is needed in the case of receiving other treatments, such as ablation chemotherapy or total body irradiation, and the bone marrow cell after processing can
To be stored in the liquid nitrogen Medical Devices of qualification.
During for internal clinical practice, the conjugated body medicine connected by the chain junctor of the present invention will be with solution or can be sterile
The form for the lyophilized solid injected after water dissolving provides.Suitable conjugation drug administration embodiment of the method is as follows:It is every to be conjugated medicine
Week by being injected intravenously once, continued for 8 weeks.Single dose is by being dissolved in 50 to 500 milliliters of physiological saline, physiology salt
Water can add human serum albumins (for example, concentration human serum albumins of 0.5 to 1 milliliter of 100mg/ml).Drug dose
It is probably per week per kg body weight in 50 μ g to 20mg, it is injected intravenously (per injection 10ug to 200mg/kg weight).8 weeks control
After treatment, patient can receive the treatment of a new round again.Detailed treatment method includes method of administration, excipient, diluent,
Drug dose, treatment time etc. can be determined by experienced clinician.
Cell mass can be killed by vivo or in vitro method choice includes any species to treat the example of disease
Malignant tumour, autoimmune disease, graft rejection and infection (including virus, bacterium or parasite) disease.
The amount for the conjugation medicine for reaching preferable biology effect and needing, will be different because of Multiple factors, these factors
The bioavilability of property feature including compound, curative effect and conjugation medicine, the type of disease, the race of patient, patient suffer from
The state of disease, the approach of administration, all of these factors taken together together decide on administration time table and administering mode.
Generally, can be by with 0.1 to 10% mass volume ratio by the conjugation medicine of the chain link in the present invention
It is dissolved in physiological buffer and is used for parenterai administration.Typical drug dose scope is from 1ug to 0.1g per kg body weight per day;
Children's dosage of the drug dose scope of recommendation every kg body weight per day or dose,equivalent from 0.01mg to 20mg.That recommends gives
Dose depends on multiple variables, including disease or the type of dysfunction, the overall health status of individual patient, coupling drug
Relative biological activity, the formulation of compound, the mode (intravenous injection, intramuscular injection, or other) of administration, is choosing administration
Pharmacokinetic properties under mode, and administration speed (single injection or continuous drip) and be administered timetable (
The number of repeat administration in certain time).
It can be equally administered by the conjugation medicine of the chain link of the present invention in the form of unit dose, " unit dose here
Amount " refers to the dosage of patient's single administration, and the medicine of unit dose simply and easily can be packed and used, unit dose
Medicine be to maintain physics and chemically stable activity conjugation medicine in itself, or as introduced below pharmaceutically acceptable
Mixture.The dosage range of typical one day is from 0.01mg to 100mg per kg body weight.In general, people is daily, or weekly,
Or every two weeks, or unit dosage ranges monthly are from 1mg to 3000mg.The unit dosage ranges of recommendation are 1mg to 500mg, often
Its administration one to four times, or more preferably 10mg to 600mg, once a day.The conjugation medicine of the present invention can pass through addition
One or more pharmaceutically acceptable auxiliary materials, are made pharmaceutical preparation administration.The medicine of this unit dose can be used for taking orally
Administration, for example be tablet, simple capsule or soft capsule;Or intranasal administration, such as powdered, nasal drop, or spray;Or
By percutaneous drug delivery, such as topical ointments, cream, washing lotion, gelling agent or spray or dermal patch.
Medicine/cytotoxic molecule
Medicine refers to can be directly or after modification by the small-molecule drug bag of the invention being connected on cell-binding molecules
Include cytotoxin.Here " small-molecule drug " widely refer to molecular weight 100 to 1800 it is organic, it is inorganic or organic
The compound of metal, more appropriate molecular weight are that 120 to the 1400. more preferable definition for small-molecule drug may refer to
WO05058367A2 and United States Patent (USP) No.4,956,303, and other documents, the here definition of small-molecule drug include institute
There is definition of the bibliography to small-molecule drug.Here medicine includes all known medicines and be likely to become medicine
Medicine.
Known medicine includes, but not limited to
1) chemotherapeutic agents reagent a) alkylating reagents:Such as nitrogen mustards:Chlorambucil, Chlornaphazine, ring phosphinylidyne
Amine, Dacarbazine, estramustine, ifosfamide, mechlorethamine, Mechlorethaminoxide Hydrochloride, mannomustin, dibromo sweet dew
Alcohol, melphalan, mitolactol, pipobroman, novembichin, phenesterin, pennisetum mustard, thiotepa, trofosfamide, urine are phonetic
Pyridine mustargen;CC-1065 (including its Ah more carrys out star, card folding comes star, Bizelesin synthetic analogues);Times carcinomycin (including close
Into analog KW-2189 and CBI-TMI);Benzodiazepine dimer (such as pyrrolo- Benzodiazepine (PBD), or tomamycin,
The dimer of indoline and Benzodiazepine, imidazo Benzodiazepine, or oxazolidine and Benzodiazepine);Nitroso ureas:(card is not
Take charge of spit of fland, lomustine, chloramphenicol, Fotemustine, Nimustine, Ranimustine);Sulfonic acid alkyl ester:(busulfan, treosulfan, English
Third Shu Fan and A-20968);Triazenes:(Dacarbazine);Compound containing platinum:(carboplatin, cis-platinum, oxaliplatin);Aziridines:
Such as Benzodepa, carboquone, Meturedepa and uredepa;Ethylenimine and methyl melamine class, including hemel, three
Ethylene melamine, triethylene glycol phosphamide, triethyl group thio-phosphamide and trimethylol melamine];B) plant alkaloids:Such as length
Spring flower alkaloid:(vincristine, vincaleukoblastinum, eldisine, vinorelbine, vinorelbine);Bearing taxanes:It is (purple
China fir alcohol, Docetaxel) and the like, maytansinoid (DM1, DM2, DM3, DM4, maytansine and ansamitocin) and
Its analog, cryptophycin (particularly cryptophycin 1 and cryptophycin 8);Epothilones, Eleutherobin, circle suberite lactone, careless tongue
Worm element, his fourth of more Rosss, Ali's statin, tubulysins, Cephalostatins;Water ghost any of several broadleaf plants alkali;Coral element A;Sponge suppresses
Element;C) .DNA topoisomerase enzyme inhibitors:Such as [epipodophyllins:(9-aminocamptothecin, camptothecine, crisnatol are soft
Erythromycin, Etoposide, etoposide phosphate, Irinotecan, mitoxantrone, mitoxantrone hydrochloride, retinoic acid (retinol), is replaced
Buddhist nun moors glycosides, topotecan, 9-nitrocamptothecin (RFS2000));Mitomycin:(mitomycin C)];D) antimetabolites:Such as
{ [anti-folic acid:Dihydrofolate reductase inhibitor (methotrexate, Trimetrexate, denopterin, pteropterin, aminopterin (4-
Amino pteroic acid) or other folacins);IMP dehydrogenase inhibitor:(mycophenolic acid, formamido thiazole, Ribavirin,
EICAR) ribonucleotide reductase inhibitors:(hydroxycarbamide, Deferoxamine)];[pyrimidine analogue:Uracil analogues:(ring born of the same parents
Glycosides, azacitidine, 6-aza uridine, capecitabine (Xeloda), Carmofur, cytarabine, di-deoxyuridine, deoxidation fluorine urine
Glycosides, Enocitabine, 5 FU 5 fluorouracil, floxuridine, draws Thailand Qu Ke (Raltitrexed));Analogue of cytosine:(cytarabine, cytimidine
Arabinoside, fludarabine);Purine analogue:(imuran, fludarabine, purinethol, thiamiprine, sulphur bird are fast
Purine)];Folic acid supplement, such as folinic acid };E) hormonotherapies:Such as { receptor antagonist:[antiestrogenic:(megestrol acetate, Lei Luo
Former times is fragrant, tamoxifen);LHRH activators:(Goserelin, leuprorelin acetate);Antiandrogen:(Bicalutamide, Flutamide,
Clausterone, dromostanolone propionate, epithio, Goserelin, leuprorelin acetate, Mepitiostane, Nilutamide, Trilostane and its
Its androgen Testolactone, inhibitor)];Vitamin A acid/deltoid muscle:[vitamin D 3 analogs (CB 1093, EB1089KH 1060,
Vitamin D3, calciferol);Photodynamic therapy:(Verteporfin, phthalocyanine, photosensitizer PC4, de-methoxy hypocrellin A);Carefully
Intracellular cytokine (interferon-' alpha ', interferon-γ, tumor necrosis factor (TNFs)), the protein of the mankind in the domain containing TNF) };F) kinases
Inhibitor, such as BIBW 2992 (anti-EGFR/Erb2), Imatinib, Gefitinib, piperazine Jia Tani, Sorafenib, Dasatinib,
Sutent, Tarceva, nilotinib, Lapatinib, Axitinib, pazopanib, Vande Thani, E7080 are (anti-
VEGFR2), Mubritinib, Ponatinib (AP24534), Ba Fei replace Buddhist nun (INNO-406), posupini (SKI-606), and card is won
For Buddhist nun, vismodegib, Iniparib, star bright Ai Ke, CYT387, Axitinib, for Fu Zhani, Sorafenib, bevacizumab, west
Appropriate former times monoclonal antibody, Herceptin, ranibizumab, Victibix, her Buddhist nun fill in;G) antibiotic, such as Enediyne Antibiotic (such as
Calicheamycin, especially calicheamicin γ 1, δ 1, α 1 and β 1, are shown in example, J.Med.Chem., 39 (11), 2103-2117 (1996),
Angew Chem Intl.Ed.Engl.33:183-186(1994);Anthracycline antibiotic dynemicin, including dynemicin
A and deoxydynemicin, Ai Sipeila mycin, Kedarcidin, C-1027, maduropeptin, and neocarzinostatin hair
Color group and its corresponding chromoprotein Enediyne Antibiotic chromomophores), aclacinomysins, D actinomycin D,
Authramycin, azaserine, bleomycin A5, act-C, carabicin, carminomycin, carzinophillin;Chromomycin, more
Mildew element, daunomycin, Detorubicin, 6- diazonium -5- oxn-l-norieucins, adriamycin, morpholine adriamycin, cyano group morpholine
Adriamycin, 2- pyrrolinodoxorubicins and deoxidation adriamycin, epirubicin, esorubicin, idarubicin, marcellomycin, mitogen
Mycin, mycophenolic acid, nogalamycin, olivomycin, Peplomycin, potfiromycin, puromycin, triferricdoxorubicin, Luo Duo
Than star, streptonigrin, streptozotocin, tubercidin, ubenimex, Zinostatin, zorubicin;H) other:Such as polyketone
Its octanone of its pungent and Bradley of compound (acetyl matches somebody with somebody base class), particularly Bradley;Gemcitabine, epoxomicins (Ka Feizuo meter), boron
Bortezomib, Thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-
9090, Stimuvax, allovectin-7, Xegeva, Provenge, Yervoy, (such as him is cut down in Lip river to isoprenylation inhibitor
Spit of fland), dopaminergic neurotoxin (such as 1-methyl-4-phenylpyridinium ion), cell cycle inhibitor (such as staurosporin), puts
Line rhzomorph (such as actinomycin D, D actinomycin D), bleomycin A5 (such as bleomycin Bleornycin A2, B2, Peplomycin), anthracene nucleus
Class medicine (such as daunorubicin, adriamycin (adriamycin), idarubicin, Epi-ADM, pirarubicin, daunorubicin benzene
Hydrazone, mtoxantrone, MDR inhibitor (such as Verapamil), Ca2+ATP enzyme inhibitors (such as thapsigargin), histone goes second
Deacerylase inhibitors (vorinostat, romidepsin, pabishta, valproic acid, mocetinostat (MGCD0103),
Belinostat, PCI-24781, entinostat, SB939, resminostat, givinostat, AR-42, CUDC-10, trailing plants
Foretell thionin, Trichostatin A);Thapsigargin, celecoxib, glitazone, Epigallo-catechin gallate (EGCG), double sulphur
Logical sequence, salinosporamideA.;Antiadrenals, such as aminoglutethimide, mitotane, Trilostane;Aceglatone;Aldehyde phosphorus
Acid amides glucosides;Levulic acid;Acridine;Cytarabine, bestrabucil;Bisantrene, edatraxate;defofamine;Autumn waters -- limid eyes
Celestial alkali;Phenodiazine compound;Eflornithine (DFMO), elfomithine;Elliptinium Acetate, etoglucid;Gallium nitrate;
Gacytosine, hydroxycarbamide;Ibandronate, lentinan;Lonidamine;Methyl-GAG;Mitoxantrone;Mopidamol;
nitracrine;Pentostatin;Phenamet;Pirarubicin;Podophyllic acid;Ethyl hydrazine;Procarbazine;Razoxane;Root nodule
Rhzomorph;Sizofiran;Spirogermanium;Tenuazonic acid;Triethyleneiminobenzoquinone;;2,2 ', 2 "-trichlorotriethylamine;(particularly T-2 poison
Element, single-ended spore myconomycin A, roridina A and anguidine);Urethanes, siRNA, antisense drug, and nucleolytic enzyme.
2) a kind of anti-autoimmunity disease agent of includes, but not limited to cyclosporine, ciclosporin A, imuran, aminocaproic acid,
Bromocriptine, Chlorambucil, chloroquine, endoxan, glucocorticoid (such as amcinonide, betamethasone, budesonide, fluorine Buddhist nun
Shrinkage porosite, hydrocortisone, fluticasone propionate, fluocortolone, dexamethasone, Triamcinolone acetonide, beclomeasone propionate), dehydrogenation table is male
Ketone, enanercept, hydroxychloroquine, infliximab, Meloxicam, methotrexate (MTX), mycophenolate mofetil, sirolimus, he
Ke Mosi, prednisone.
3) resistant to infection disease agent includes, but not limited to a) aminoglycosides:Amikacin, Astromicin, celebrating are big mould
Plain (Netilmicin, sisomicin, Isepamicin), hygromycin B, kanamycins (Arbekacin, amikacin, kanamycin B,
Dibekacin, tobramycin), neomycin, (paromomycin, neomycin b, ribostamycin), and netilmicin, spectinomycin,
Streptomysin, tobramycin, verdamicin;B) chloromycetin series antibioticses class:Azidamfenicol, chloramphenicol, Florfenicol,
Thiamphenicol;C) Ansamycins class:Geldanamycin, herbimycin;D) carbapenem antibiotics class:Compare A Pei
South, donipenem, ertapenem, Imipenem/cilastatin, Meropenem, Panipenem;E) cephalo-types:Carbacephem
(Loracarbef), Cefacetrile, Cefaclor, Cefradine, cefadroxil, cefalonium, cefaloridine, cephalothin or
Cefoxitin, cefalexin, cefaloglycin, cefadole, cefapirin, cefatrizine, Cefazaflur, Cefazedone, cephalo
Oxazoline, cefbuperazone, Cefcapene, Cefdaloxime, Cefepime, Cefminox, Cefoxitin, Cefprozil, cefroxadine,
Ceftezole, cefuroxime, Cefixime, Cefdinir, cefoperon, cefetamet, Cefmenoxime, Cefodizime, cephalo
Ni Xi, cefoperazone, ceforanide, cefotaxime, Cefotiam, Cefozopran, Cefpimizole, cefpiramide, Cefpirome,
Cefpodoxime, Cefquinome, Cefsulodin, cefotaxime, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, cephalo
Pyrrole is general, ceftriaxone, cefuzonam, cephamycin (Cefoxitin, cefotetan, cefmetazole), oxacephem (Flomoxef,
Latamoxef);F) glycopeptides class:Vancomycin (bleomycin, oritavancin, Te Lawan stars), teicoplanin (Dalbavancin),
Ramoplanin;G) glycyl ring class:Such as tigecycline;H) beta-lactamase inhibitors class:Penam (Sulbactam, his azoles bar
It is smooth), clavam (clavulanic acid);I) LIN Keshengs:Clindamycin, lincomycin;J) lipopeptids:Daptomycin, A54145,
Ca-dependent antibiotic (CDA);K) macrolide antibiotics erythromycin, azithromycin, clarithromycin, Dirithromycin are red mould
Element, roxithromycin, josamycin, ketone lactone (Ketek, cethromycin), medecamycin, methomycin, oleandomycin, profit
Good fortune mycin (rifampin, Mycobutin, Rifapentine), rokitamycin, roxithromycin, spectinomycin, spiramvcin, tacrolimus
(FK506), troleandomycin, Ketek;L) monobactamses:Aztreonam, tigemonam, m) oxazolidinones:
Linezolid;N) penicillin antibiotics:Amoxicillin, ampicillin (Pivampicillin, hetacillin, Bacampicillin, Mei Tan
XiLin, Talampicillin), azidocillin, azlocillin, benzyl penicillin, tardocillin, tardocillin, benzyl star Phenoxymethyl green grass or young crops
Mycin, clometocillin, procaine benzylpenicillinate, carbenicillin (carindacillin), Cloxacillin, dicloxacillin, according to a west
Woods, flucloxacillin, Mecillinam (Pivmecillinam), mezlocillin, methicillin, naphthlazole, oxacillin, penamecillin, disk
Buddhist nun XiLin, pheneticillin, ospen, Piperacillin, propicillin, sulbenicillin, temocillin, Ticarcillin;O) polypeptides
Class:Bacitracin, colistin, polymyxin B;P) quinolones:Alafloxacin, Balofloxacin, Ciprofloxacin, Clinafloxacin,
Enoxacin, Enrofloxacin, Danofloxacin, Difloxacin, Ofloxacin, T-3811, gatifloxacin, gemifloxacin, Ge Pa
Sha Xing, Kano trovafloxacin, lavo-ofloxacin, Lomefloxacin, marbofloxacin, Nadifloxacin, Moxifloxacin, Orbifloxacin, promise
Flucloxacillin, Ofloxacin, Pefloxacin, trovafloxacin, sitafloxacin, Sparfloxacin, Grepafloxacin, Temafloxacin, support fluorine are husky
Star, trovafloxacin;Q) sun bacteriums:Pristinamycin, Quinupristin/Dalfopristin) r) sulfamidos:Mafenide, azo sulphur
Amine, sulfacetamide, sulfamethizole, salicylazosulfapyridine, bacteresulf, trimethoprim, sulfamethoxazole (the new promise of compound
It is bright);S) steroids antimicrobial:For example, Fusidic Acid;T) tetracycline antibiotics:Doxycycline, chlorine hydroxytetracycline, chlorine four
Ring element, lymecycline, demethylchlortetra cylinum, terramycin, minocycline, chloromethoxazole, oxytetracycline, penimepicycline, pyrrole first
Tetracycline, tetracycline, glycyl (such as tigecycline);U) antibiotic of others type:Annonacin, Arsphenamine, carefully
Bacterium terpene alcohol inhibitor (bacitracin), DADAL/AR inhibitor (seromycin), dictyostatin, circle suberite lactone, end pomegranate
It is plain to fill in Lip river, Epothilones, ethambutol, Etoposide, faropenem, Fusidic Acid, furazolidone, isoniazid,
Laulimalide, metronidazole, mupirocin, mycolactone, NAM synthetic inhibitors (such as phosphonomycin), Nitrofurantoin,
Taxol, tablet mycin, pyrazinamide, Quinupristin/Dalfopristin, rifampin (rifampicin), Tazobactam Sodium sulphur first
Nitre imidazoles, Annona lactone;
4) antiviral drugs:A) inputs/fusion inhibitor:Aplaviroc, maraviroc, Vicriviroc, gp41
(T-20), PRO 140, CD4 (ibalizumab);B) integrase inhibitors:Merck, angstrom for draw Wei, glo
boidnan A;C) maturations inhibitor:Bevirimat, vivecon;D) neuraminidase inhibitors:Oseltamivir, Zha Na meter
Wei, Peramivir;E) nucleosides and nucleotide:Abacavir, acyclovir, Aldoforwe ester, amdoxovir, A Purui west he
Shore, Brivudine, cidofovir, right Elvucitabine, Clevudine, Didanosine (DDI), Elvucitabine, emtricitabine (FTC),
Entecavir, famciclovir, fluorouracil (5-FU), 3 '-fluoro- substituted 2 ', 3 '-di-deoxynucleoside analog, (for example,
3 '-fluoro- 2 ', 3 '-Didansine (FLT), 3 '-fluoro- 2 ', 3 '-dideoxyguanosine (FLG), Fomivirsen, Ganciclovir, iodine
Glycosides, Lamivudine (3TC), 1- nucleosides (such as β-l- thymidines and β-l-2 '-deoxycytidine) Penciclovir, racivir, Li Ba
Wei Lin, stampidine, stavudine (d4T), tarib avirin (viramidine), Sebivo, tenofovir, three cut down
VACV, valganciclovir, zalcitabine (DD C), Zidovudine (AZT);F) non-nucleosides medicine:Amantadine,
Ateviridine, capravirine, Diarylmiazines compound (etravirine, rilpivirine), Delavirdine, 22 alcohol, second
Meter Wei Lin, efavirenz, phosphonic acid (phosphonic acid), imiquimod, alfa-interferon, Loviride, lodenosine, methisazone,
Nevirapine, nov-205, Peg-IFN alpha-2b alfa, podophyllinic acid lactone, rifampin, rimantadine, resiquimod (R-
848), g) protease inhibitors:Anpunave, atazanavir, Bo Saipowei, darunavir, fosamprenavir, indinavir, Lip river
That Wei, Nai Feinawei, Ritonavir, pula Sean Connery, inverase, telavi (VX-950), tipranavir;H) its
His type antiviral drugs:Abzyme, Abiduoer, poon lactone A, ceragenin, Cyanovirin-N, diaryl are phonetic
Pyridine class compound, Epigallo-catechin gallate (EGCG) (EGCG), phosphonic acid, griffithsin, Ta Liweilin
(viramidine), hydroxycarbamide, kp-1461, Miltefosine, pula Sean Connery, portm anteau inhibitors, Li Ba
Wei Lin, Seliciclib.
5) medicine linked in the present invention by hydrophilic connector further includes following radio isotope.Example radioactivity
Isotope (radionuclide) is3H,11C,14C,18F,32P,35S,64Cu,68Ga,86Y,99Tc,111In,123I,124I,125I,131I
,133Xe,177Lu,211At, and213Bi.The antibody of labelled with radioisotope is highly useful in receptor target imaging experiment or can
Targetedly targeted therapy is directly used in, such as invention (Wu et al (2005) Nature of antibody drug conjugate
Biotechnology 23(9):1137-1146).The molecule of cell combination, such as antibody, as previously mentioned:It can pass through
This patent hydrophilic chain junctor combines, chelates or form other complicated radioisotope metals combinations to be labeled, this
Labelling technique is described in Current Protocols in Immunology, Volumes 1and 2, Coligen et al,
Ed.Wiley-Interscience,New York,N.Y.,Pubs.(1991).The chelating agent of complicated metal complex can be generated
Including DOTA, DOTP, DOTMA, DTPA and TETA (Macrocyclics, Dallas, Tex.)
6) derivative of the pharmaceutically acceptable salt of any of the above described compound, acid and any of the above described medicine.
This patent is connected to the cytotoxic drugs of cell-binding molecules preferably through this hydrophilic chain junctor conjugation
The compound of tubulysins, CHROMATOGRAPHIC FRACTIONATION AND MASS, taxanoids (taxol), CC-1065 analogs, daunorubicin and adriamycin,
Benzodiazepines dimer is (for example, pyrrolo- Benzodiazepine (PBD) dimer, tomamycin dimer, anthramycin dimerization
The dimer of body, indoline and Benzodiazepine dimer, imidazo Benzodiazepine dimer, or oxazolidine and Benzodiazepine),
Calicheamycin and Enediyne Antibiotic, D actinomycin D, azaserine (azaserines), bleomycin, epirubicin (table
Adriamycin), tamoxifen, idarubicin, aplysiatoxin (the dolastatin)/auspicious statin of Austria (such as monomethyl auspicious statin difficult to understand
E, MMAE, MMAF, auspicious statin PYE difficult to understand, auspicious statin TP difficult to understand, auspicious statin 2-AQ, 6-AQ, EB (AEB) difficult to understand, and EFP
(AEFP)), block meter Xing, phosphinothioylidynetrisaziridine, vincristine, hemiasterlins, esperamicins, and their analog more
And derivative.
In another embodiment, the medicine in formula (II) and (IV) can be chromophore molecule, its conjugate can use
In detection, monitoring or the interaction of research cell-binding molecules and target cell.Chromophore molecule is with a kind of light of absorption
The compound of ability, such as ultraviolet light, fluorescence, infrared light, near infrared light, it is seen that light;Pigment molecular includes uranidin, red blood cell life
The classification or subclass of thing, iris pigment, leucocyte, melanocyte and large cortical cells;The classification or subclass of fluorophore molecule, it is
Fluorescence chemical compound shines again under light;The classification or subclass of visual light transduction molecule;Shine photon molecule one kind or
Subclass;One kind or subclass of chemiluminescence molecule;With the classification or subclass of Fluorescein compound.
Chromophore molecule may be selected from but be not limited to nonprotein organic fluorescence group, such as:Xanthene derivative (fluorescein,
Rhodamine, Oregon is green, Yihong and texas Red);Cyanine derivative thing:(cyanine, indoles carbocyanine, oxa- cyanine, thio flower
Blue or green and merocyanine);Side's acid cyanines derivative and cyclosubstituted side's acid cyanines, including Seta, SeTau and Square dyestuffs;Naphthalene derivatives
(dansyl and prodan derivatives);Coumarin derivative;Oxadiazole derivatives (pyrido oxazole, nitrobenzoxadiazole and benzene
And oxadiazoles);Anthracene derivant (Anthraquinones, including DRAQ5, DRAQ7 and CyTRAK oranges);Pyrene derivatives (cascade blue etc.);Oxazines
Derivative (Nile red, Nile blue, cresol-purple, oxazines 170 etc.);Acridine derivatives (proflavin flavine, acridine orange, acridine
Huang etc.);Arylmethylamine derivative (auramine, crystal violet, malachite green);Tetrapyrrole derivative (porphines, phthalocyanine, bilirubin);Or
Chromophore molecule can be selected from any analogs and derivatives of following fluorophore compounds:CF dyestuffs (Biotium), DRAQ and
CyTRAK probes (BioStatus), BODIPY (Invitrogen), Alexa Fluor (Invitrogen), DyLight
Fluor (Thermo Scientific, Pierce), Atto and Tracy (Sigma Aldrich), FluoProbes
(Interchim), Abberior dyestuffs (Abberior), DY and MegaStokes dyestuff (Dyomics), sulfo group Cy dyestuffs
(Cyandye), HiLyte Fluor (AnaSpec), Seta, SeTau and Square dyestuffs (SETA BioMedicals),
Quasar and Cal Fluor dyestuffs (biological research and development technology company), SureLight dyestuffs (APC, RPEPerCP,
Phycobilisomes) (Biological Science Co., Ltd of Colombia), APC, APCXL, RPE, BPE (Phyco-Biotech);
The example for linking precursor reactant or the fluorophore compounds that can be coupled with the present invention is allophycocyanin (APC), ammonia
Butylcoumariii, APC-Cy7 conjugates, BODIPY-FL, Cascade are blue, Cy2, Cy3, Cy3.5, Cy3B, Cy5, Cy5.5, Cy7,
Fluorescein, FluorX, Hydroxycoumarin, Sulforhodamine B, lucifer yellow, Methoxycoumarin, NBD, the Pacific Ocean is blue, too
Flat ocean orange, PE-Cy5 conjugates, PE-Cy7 conjugates, PerCP, R-PE (PE), Red 613, Seta-555- nitrine,
Seta-555-DBCO, Seta-555-N- HOSu NHS, Seta-580-N- HOSu NHSs, Seta-680-N-
HOSu NHS, Seta-780-N- HOSu NHSs, Seta--APC-780, Seta-PerCP-680, Seta-R-
PE-670, SeTau-380-N- HOSu NHS, SeTau-405- maleimides, SeTau-405-N- hydroxysuccinimidyl acyls
Imines, SeTau-425-N- HOSu NHSs, SeTau-647-N- HOSu NHSs, Texas Red, TRITC,
TruRed, X- rhodamine.
The fluorophore compounds for being used to study nucleic acid or protein that can be connected with the chain junctor of the present invention are selected from following
Compound or derivatives thereof:7-AAD (7-aminoactinomycin D, CG- selectivity), acridine orange, pigment-A3, CyTRAK orange
(Biostatus, red excitation are black), DAPI, DRAQ5, DRAQ7, ethidium bromide, Hoechst33258, Hoechst33342,
LDS 751, mithramycin, propidium iodide (PI), SYTOX is blue, and SYTOX is green, SYTOX oranges, thiazole orange, TO-PRO:Cyanine monomer,
TOTO-1, TO-PRO-1, TOTO-3, TO-PRO-3, YOSeta-1, YOYO-1.The use that can be connected with the chain junctor of the present invention
Following compounds or derivatives thereof are selected from the fluorophore compounds of research cell:DCFH (2,7 ,-dichlorofluorescin, oxygen
Change form), DHR (dihydro Rhodamine 123, oxidised form, light cat agent oxidation), Fluo-3 (AM esters, pH>6), Fluo-4
(AM esters, pH7.2), Indo-1 (AM esters, low high calcium (Ca 2+)), SNARF (pH 6/9).It can connect with the chain junctor of the present invention
The fluorophore compounds for being used to study protein/antibody connect are selected from following compounds or derivatives thereof:Allophycocyanin
(APC), AmCyan1 (tetramer, Clontech), AsRed2 (tetramer, Clontech), Azami Green (single aggressiveness,
MBL),Azurite,B-phycoerythrin(BPE),Cerulean,CyPet,DsRed monomer(Clontech),
DsRed2 (" RFP ", Clontech), EBFP, EBFP2, ECFP, EGFP (weak dimer, Clontech), Emerald companies
(Emerald companies), luciferin B (phycoerythrin) weak dimer, Invitrogen), EYFP (weak dimer, Clontech),
Green fluorescent protein (S65A mutation), green fluorescent protein (S65C mutation), green fluorescent protein (S65L mutation), green fluorescence
Albumen (S65T mutation), green fluorescent protein (Y66F mutation), green fluorescent protein (Y66H mutation), green fluorescent protein
(Y66W mutation), green fluorescent protein uv, HcRed1, J-Red, Ka Tusha, card figure husky of common dye (monomer, MBL), mCFP, mCher-
Ry, mCitrine, Midoriishi cyan (dimer, MBL), mKate (TagFP635, monomer, Evrogen), mKeima-
Red (monomer, MBL), mKO, mOrange, mPlum, mRaspberry, mRFP1 (monomer, Tsien laboratories),
MStrawberry, mTFP1, mTurquoise2, P3 (phycobilisome complex), Peridinin chlorophyll (PerCP), R- algae reds
Albumen (RPE), T-Sapphire, TagCFP (dimer, Evrogen), TagGFP (dimer, Evrogen), TagRFP (two
Aggressiveness, Evrogen), TagYFP (dimer, Evrogen), tdTomato (series connection dimer), Topaz, TurboFP602 (two
Aggressiveness, Evrogen), TurboFP635 (dimer, Evrogen), TurboGFP (dimer, Evrogen), TurboRFP (two
Aggressiveness, Evrogen), TurboYFP (dimer, Evrogen), Venus, wild type GFP, YPet, ZsGreen1 (tetramer,
Clontech), ZsYellow1 (tetramer, Clontech).
In another embodiment, the preferred thin of cell-binding molecules is coupled to by the hydrophily chain junctor of this patent
Cellular toxicity agent is tubulysins, maytansinoid, taxanes (taxane), CC-1065 analogs, daunorubicin and
Doxorubicin compound, Benzodiazepines dimer (such as pyrroles's Benzodiazepine dimer, tomaymycin dimer, Anthramycin
Dimer, indoline Benzodiazepine dimer, imidazoles Benzodiazepine dimer, oxazoline Benzodiazepine dimer), Jia Liche is mould
Element and enediyne antibiotic, D actinomycin D, azaserine, bleomycin, epirubicin, tamoxifen, idarubicin, Duola
Department's statin, the auspicious statin of Austria (such as monomethyl Austria auspicious statin E, MMAE, MMAF, auspicious statin PYE difficult to understand, auspicious statin TP, Ao Ruita difficult to understand
Spit of fland 2-AQ, 6-AQ, EB (AEB) and EFP (AEFP)), Ka-7038Ⅶ of shutting out, thiotepa, vincristine, Ban meter Tallins,
Nazumamides, micro- wheat globulin, radiosumins, alterobactins, microsclerominmins,
Theonellamides, esperamicins, PNU-159682 and the like and and its derivative.
It is well known in the art and can be according to known method from natural that preferable Tubulysins is coupled in the present invention
Source separation or synthetically prepared (for example, Balasubramanian, R. according to known method;et al.J.Med.Chem.,
2009,52,238–240.Wipf,P.;et al.Org.Lett.,2004,6,4057–4060.Pando,O.;et
al.J.Am.Chem.Soc.,2011,133,7692–7695.Reddy,J.A.;et al.Mol.Pharmaceutics,2009,
6,1518–1525.Raghavan,B.;et al.J.Med.Chem.,2008,51,1530–1533.Patterson,A.W.;et
al.J.Org.Chem.,2008,73,4362–4369.Pando,O.;et al.Org.Lett.,2009,11(24),pp
5567–5569.Wipf,P.;et al.Org.Lett.,2007,9(8),1605–1607.Friestad,G.K.;
Org.Lett.,2004,6,pp 3249–3252.Hillary M.Peltier,H.M.;et al.J.Am.Chem.Soc.,
2006,128,16018–16019.Chandrasekhar,S.;et al.J.Org.Chem.,2009,74,9531–
9534.Liu,Y.;et al.Mol.Pharmaceutics,2012,9,168–175.Friestad,G.K.;et
al.Org.Lett.,2009,11,1095–1098.Kubicek,K.;et al.,Angew Chem Int Ed Engl,
2010.49:p.4809-12.Chai,Y.;et al.,Chem Biol,2010,17:296-309.Ullrich,A.;et al.,
Angew Chem Int Ed Engl,2009,48,4422-5.Sani,M.;et al.Angew Chem Int Ed Engl,
2007,46,3526-9.Domling,A.;et al.,Angew Chem Int Ed Engl,2006.45,7235-9.Patent
applications:Zanda,M.;et al,Can.Pat.Appl.CA 2710693(2011).Chai,Y.;et
al.Eur.Pat.Appl.2174947(2010),PCT WO 2010034724.Leamon,C.;et al,PCT WO
2010033733,WO 2009002993.Ellman,J.;et al,PCT WO 2009134279;PCT WO 2009012958,
US appl.20110263650,20110021568,Matschiner,G.;et al,PCT WO 2009095447.Vlahov,
I.;et al,PCT WO 2009055562,WO 2008112873.Low,P.;et al,PCT WO
2009026177.Richter,W.,PCT WO 2008138561.Kjems,J.;et al,PCT WO
2008125116.Davis,M.;et al,PCT WO2008076333.Diener,J.;et al,
U.S.Pat.Appl.20070041901,WO 2006096754.Matschiner,G.;et al,PCT WO
2006056464.Vaghefi,F.;et al,5PCT WO 2006033913.Doemling,A.,Ger.Offen.DE
102004030227;PCT WO 2004005327;WO 2004005326;WO2004005269.Stanton,M.;et al,
U.S.Pat.Appl.Publ.20040249130.Hoefle,G.;et al,Ger.Offen.DE 10254439;DE
10241152;DE 10008089.Leung,D.;et al,WO 2002077036.Reichenbach,H.;et al,
Ger.Offen.DE 19638870;Wolfgang,R.;US 20120129779,Chen,H.,US appl.20110027274.
The preferential Tubulysin structures for coupled cell binding molecule are described in patent application PCT/IB2012/053554.
The preferable Calicheamicin of cell-binding molecules-drug conjugates and its related enediyne antibiosis on this patent
Sketch is set forth in:Nicolaou, K.C. et al., Science 1992,256,1172-1178;Proc.Natl.Acad.Sci
USA.1993,90,5881-5888),U.S.Patent Nos.4,970,198;5,053,394;5,108,912;5,264,
586;5,384,412;5,606,040;5,712,374;5,714,586;5,739,116;5,770,701;5,770,710;5,
773,001;5,877,296;6,015,562;6,124,310;8,153,768.
Preferable maytenin applied to this patent includes maytansinoid and maytansinoids like thing
It is described in U.S. Patent number:4,256,746,4,361,650,4,307,016,4,294,757,4,294,757,4,371,533,
4,424,219,4,331,598,4,450,254,4,364,866,4,313,946,4,315,929 4,362,663,4,322,
348,4,371,533,4,424,219,5,208,020,5,416,064,5,208,020;5,416,064;6,333.410;6,
441,163;6,716,821,7,276,497,7,301,019,7,303,749,7,368,565,7,411,063,7,851,
432, and 8,163,888. cytotoxicity natural products taxol alkane include taxol (taxol) and semi-synthetic Docetaxel
(taxotere) and the like preferably carries out preparation coupling by the hydrophily connexon of this patent.It for example exists:K
C.Nicolaou et al., J.Am.Chem.Soc.117,2409-2420, (1995);Ojima et al., J.Med.Chem.39:
3889-3896(1996);40:267-278(1997);45,5620-5623(2002);Ojima et al.,
Proc.Natl.Acad.Sci.,96:4256-4261(1999;Kim et al., Bull.Korean Chem.Soc., 20,1389-
1390(1999);Miller, et al., J.Med.Chem., 47,4802-4805 (2004);U.S. Patent number 5,475,011 5,
728,849,5,811,452;6,340,701;6,372,738;6,391,913,6.436,931;6,589,979;6,596,
757;6,706,708;7,008,942;7,186,851;7,217,819;7,276,499;7,598,290;and 7,667,
054.
CC-1065 analogs and the mould analogs of Du Ka preferably by the hydrophily connexon of this patent prepare even
Connection.CC-1065 analogs and the mould analog examples of Du Ka and their synthesis are described as follows:Warpehoski et al,
J.Med.Chem.31:590-603(1988),D.Boger et al.,J.Org.Chem;66;6654-6661,2001;
U.S.Patent Nos:4169888,4391904,4671958,4816567,4912227,4923990,4952394,
4975278,4978757,4994578,5037993,5070092,5084468,5101038,5117006,5137877,
5138059,5147786,5187186,5223409,5225539,5288514,5324483,5332740,5332837,
5334528,5403484,5427908,5475092,5495009,5530101,5545806,5547667,5569825,
5571698,5573922,5580717,5585089,5585499,5587161,5595499,5606017,5622929,
5625126,5629430,5633425,5641780,5660829,5661016,5686237,5693762,5703080,
5712374,5714586,5739116,5739350,5770429,5773001,5773435,5786377 5786486,
5789650,5814318,5846545,5874299,5877296,5877397,5885793,5939598,5962216,
5969108,5985908,6060608,6066742,6075181,6103236,6114598,6130237,6132722,
6143901,6150584,6162963,6172197,6180370,6194612,6214345,6262271,6281354,
6310209,6329497,6342480,6486326,6512101,6521404,6534660,6544731,6548530,
6555313,6555693,6566336,6,586,618,6593081,6630579,6,756,397,6759509,6762179,
6884869,6897034,6946455,7,049,316,7087600,7091186,7115573,7129261,7214663,
7223837,7304032,7329507,7,329,760,7,388,026,7,655,660,7,655,661,7,906,545,and
8,012,978.
Daunorubicin/Doxorubicin analog is also preferably used for being coupled by the hydrophilic linkers of this patent.Its
Preferable structure and its synthesis example are as follows:Hurwitz,E.,et al.,Cancer Res.35,1175-1181(1975)
.Yang,H.M.,and Reisfeld,R.A.,Proc.Natl.Acad.Sci.85,1189-1193(1988);Pietersz,
C.A.,E.,etal.,E.,et al.,"Cancer Res.48,926-9311(1988);Trouet,et al.,79,626-
629(1982);Z.Brich etal.,J.Controlled Release,19,245-258(1992);Chen et al.,
Syn.Comm.,33,2377-2390,2003;King et al.,Bioconj.Chem.,10,279-288,1999;King et
al.,J.Med.Chem.,45,4336-4343,2002;Kratz et al.,J Med Chem.45,5523-33.2002;
Kratz et al.,Biol Pharm Bull.Jan.21,56-61,1998;Lau et al.,Bioorg.Med.Chem.3,
1305-1312,1995;Scott et al.,Bioorg.Med.lChem.Lett.6,1491-1496;1996;Watanabe
et al.,Tokai J.Experimental Clin.Med.15,327-334,1990;Zhou et al.,
J.Am.Chem.Soc.126,15656-7,2004;WO 01/38318;U.S.Patent No.).5,106,951;5,122,
368;5,146,064;5,177,016;5,208,323;5,824,805;6,146,658;6,214,345;7569358;7,
803,903;8,084,586;8,053,205.
Auspicious statin and dolastatin difficult to understand are also preferably used for being coupled by the hydrophilic linkers of this patent.Ao Rui
Statin (such as monomethyl auspicious statin E (MMAE) difficult to understand, monomethyl auspicious statin (MMAF) difficult to understand, auspicious statin PYE difficult to understand, auspicious statin TP difficult to understand,
Auspicious statin 2-AQ difficult to understand, 6-AQ, EB (AEB) and EFP (AEFP)
Auspicious statin and dolastatin difficult to understand are also preferably used for being coupled by the hydrophilic linkers of this patent.Ao Rui
Statin (such as auspicious statin E (AE) difficult to understand, auspicious statin EB (AEB) difficult to understand, auspicious statin EFP (AEFP) difficult to understand, monomethyl Ao Ruita
Spit of fland E (MMAE), monomethyl auspicious statin (MMAF) difficult to understand, auspicious statin F phenylenediamines (AFP) difficult to understand and MMAE phenylalanines variant) be
Dolastatin analog, document below have been reported:Int.J.Oncol.15:367-72(1999);Molecular
Cancer Therapeutics,vol.3,No.8,pp.921-932(2004);U.S. Patent Application No. 11134826,
20060074008,2006022925. U.S. Patent number 4414205,4753894,4764368,4816444,4879278,
4943628,4978744,5122368,5165923,5169774,5286637,5410024,5521284,5530097,
5554725,5585089,5599902,5629197,5635483,5654399,5663149,5665860,5708146,
5714586,5741892,5767236,5767237,5780588,5821337,5840699,5965537,6004934,
6033876,6034065,6048720,6054297,6054561,6124431,6143721,6162930,6214345,
6239104,6323315,6342219,6342221,6407213,6569834,6620911,6639055,6884869,
6913748,7090843,7091186,7097840,7098305,7098308,7498298,7375078,7462352,
7553816,7659241,7662387,7745394,7754681,7829531,7837980,7837995,7902338,
7964566,7964567,7851437,7994135.
Benzodiazepines dimer (such as pyrroles's Benzodiazepine dimer, tomaymycin dimer, Anthramycin dimerization
Body, indoline Benzodiazepine dimer, imidazoles Benzodiazepine dimer or oxazoline Benzodiazepine dimer) it is that the present invention is excellent
The dimer of the cytotoxic agent of choosing, its example:U.S. Patent number 8,163,736;8,153,627;8,034,808;7,834,
005;7,741,319;7,704,924;7,691,848;7,678,787;7,612,062;7,608,615;7,557,099;7,
528,128;7,528,126;7,511,032;7,429,658;7,407,951;7,326,700;7,312,210;7,265,
105;7,202,239;7,189,710;7,173,026;7,109,193;7,067,511;7,064,120;7,056,913;7,
049,311;7,022,699;7,015,215;6,979,684;6,951,853;6,884,799;6,800,622;6,747,
144;6,660,856;6,608,192;6,562,806;6,977,254;6,951,853;6,909,006;6,344,451;5,
880,122;4,935,362;4,764,616;4,761,412;4,723,007;4,723,003;4,683,230;4,663,
453;4,508,647;4,464,467;4,427,587;4,000,304;US patent appl.20100203007,
20100316656,20030195196.
In patent of the present invention, the analog and derivative of described cytotoxic drug/medicament can pass through the present invention
Hydrophily chain junctor reagent is coupled.In industry field, those of skill in the art are generally known to cytotoxic drug/examination
Agent with what mode modify and can keep specificity/activity of each cytotoxic drug/reagent starting.Together
Sample, the generally known many compounds of those of skill in the art can be used to substitute the cytotoxicity medicine described in patent of the present invention
Thing/medicament.Therefore, medicine/medicament in patent of the present invention includes the analog and derivative of compound described here.
Cited document and example, which are expressly incorporated into example, in patent of the present invention is illustrated.
Example
Patent of the present invention has carried out further instruction with following example, and the content of these examples does not limit the present invention specially
The scope of profit.The condition of culture of described cell line in instances, in addition to specified otherwise, is protected according to U.S.'s strain
Trained under conditions of Tibetan center (ATCC) or German Culture Collection Center (DSMZ) or Chinese Shanghai cell culture studies are specified
Support.In addition to specified otherwise, cell culture reagent comes from Invitrogen companies.All anhydrous reagents are by commercial sources
Obtain, and be stored in nitrogen-filled seal bottle.Other reagents and solvent are bought according to highest specification, without further during use
Processing.Preparation HPLC separation is carried out in Varain PreStar HPLC.Nmr spectrum is in Varian Mercury
Detection show that in units of ppm, tetramethylsilane is standard for chemical shift, and the unit of coupling constant (J) is on 400MHz instruments
Hz.Mass spectrometric data is by Waters Acquity UPLC separation modules and Acquity TUV detectors in Waters Xevo Qtof
Obtained on mass spectrum
Embodiment 1:3- (((2- (2,5- dioxy -2,5- dihydro -1H- pyrroles -1- bases) ethyl) amino) (hydroxyl) phosphinylidynes
Base) amino) propionic acid (4)
Add in THF (50ml) solution of N-2- ethyls-imide salts hydrochlorate (1.0g, 5.66mmol) of the cooling at -78 DEG C
Enter tri-chlorination phosphinylidyne (0.86g, 5.66mmol).At -78 DEG C stirring 2 it is small when with formed (2- (2,5- dioxy -2,5- dihydros -
1H- pyrroles -1- bases) ethyl) amino phosphinylidyne dichloro (2), by 3- alanines (0.51g, 5.70 mMs) in THF/H2O(2:
1,30 milliliter) it is added to triethylamine (1.0 grams, 9.90 mMs) in mixture solution in solution.Mixture stirs at room temperature
Mix 3 it is small when, be concentrated in vacuo and with H2O/CH3CN(1:20~1:10) eluting solvent is in SiO2Purified on column, obtain title compound
Thing 4 (1.28g, 78% yield).ESI MS m/z-C9H13N3O6P (M-H), calculated value 290.06, finds value 290.10.
Embodiment 2:3- ((((2- (2,5- dioxo -2,5- dihydro -1H- pyrroles -1- bases) ethyl) amino) (hydroxyl) phosphorus
Acyl group) amino) propionic acid N-hydroxy-succinamide ester.
3- ((((2- (2,5- dioxo -2,5- dihydro -1H- pyrroles -1- bases) ethyl) amino) (hydroxyl)-phosphoryl) ammonia
Base) propionic acid (4) (0.50g, 1.72mmol) DMA (30ml) solution in add NHS (0.20g, 1.74mmol) and EDC
(0.81g, 4.22mmol).Mixture is stirred overnight under Ar, is evaporated and with acetone/CH2Cl2(1:10~1:3) eluant, eluent exists
SiO2Purified in chromatography.Merge the collection liquid containing product, evaporation, in C2H5Cure in OH dioxane/hexane, obtain title
Compound (392mg, 58% yield).ESI MS m/z-C13H16N4O8P (M-H), calculated value 387.08, finds 387.20.
Embodiment 3:3- ((two ((2- (2,5- dioxo -2,5- dihydro -1H- pyrroles -1- bases) ethyl) amino)-phosphinylidynes
Base)-amino) propionic acid (8).
The THF (100ml) of the N-2- ethyl-maleimides hydrochloride (2.0g, 11.32mmol) cooled down at -78 DEG C
Tri-chlorination phosphinylidyne (0.86g, 5.66mmol) is added in solution.After when stirring 1 is small at -78 DEG C, three second are added into mixture
Amine (1.0g, 9.90mmol), and by resulting solution be stirred at room temperature 3 it is small when to produce double (2- (2,5- dioxos -2,5- bis-
Hydrogen -1H- pyrroles -1- bases) ethyl)-amino phosphoryl chloride phosphorus oxychloride (7).Then by 3- alanines (0.51g, 5.70mmol) in THF/H2O
(2:1,30ml) and in the mixture of triethylamine (1.51g, 14.90mmol) it is added in solution.By gained mixture at 35 DEG C
It is lower stirring 3 it is small when, be concentrated in vacuo, use H2O/CH3CN(1:20~1:10) eluant, eluent is in SiO2Purified on column, obtain title compound
Thing 8 (1.47g, 63% yield).ESI MS m/z-C15H19N5O7P (M-H), calculated value 412.11, finds 412.20.
Embodiment 4:3- ((double ((2- (2,5- dioxo -2,5- dihydro -1H- pyrroles -1- bases) ethyl) amino) phosphoryls)
Amino) propionic acid N-hydroxy-succinamide ester (9).
3- ((double ((2- (2,5- dioxo -2,5- dihydro -1H- pyrroles -1- bases) ethyl) amino) phosphoryls) amino)-the third
Added in the solution of sour (8) (0.55g, 1.33mmol) in DMA (30ml) NHS (0.20g, 1.74mmol) and EDC (0.78g,
4.06mmol).Mixture is stirred overnight under Ar, is evaporated and in short SiO2Purified in chromatographic column, use EtOAc/CH2Cl2(1:3
~1:1) elute.Merge the collection liquid containing product, vacuum evaporation obtains title compound (536mg, yield 79%).ESI MS
m/z+C19H23N6NaO9P (M+Na), calculated value 533.13, finds 533.20.
Embodiment 5:3- ((hydroxyl ((2- (pyridine -2- base disulphanes base) ethyl) amino) phosphoryl) amino) propionic acid
(15)。
Three are added in THF (60ml) solution of (pyridine -2- base disulphanes base) ethylamine hydrochloride (1.40g, 7.52mmol)
Phosphorus chloride (1.15g, 7.56mmol).To form (2- (pyridine -2- base disulphanes base) ethyl) ammonia when stirring 2 is small at -78 DEG C
After base phosphinylidyne dichloro (14), 3- alanines (0.67g, 7.52mmol), 30ml) in THF/H2O(2:1,30ml) solution neutralizes
Triethylamine (20g, 19.80mmol) is added in mixed solution above.Gained mixture be stirred at room temperature 3 it is small when, vacuum is dense
Contract in SiO2H is used on column2O/CH3CN(1:20~1:10) it is purified by flash, obtains title compound 15 (1.69g, 66% production
Rate).ESI MS m/z-C10H15N3O4PS (M-H), calculated value 336.03, finds 336.20.
Embodiment 6:3- ((((2- (pyridine -2- base disulphanes base) ethyl) amino)-(hydroxyl) phosphoryl) amino) propionic acid
N-hydroxy-succinamide ester (16).
3- ((((2- (pyridine -2- base disulphanes base) ethyl) amino) (hydroxyl)-phosphoryl) amino) propionic acid (15)
(0.60g, 1.78mmol) in DMA (30ml) solution add NHS (0.22g, 1.91mmol) and EDC (0.81g,
4.22mmol).Mixture is stirred overnight under Ar, evaporates and is carried out at 4 DEG C with short C-18 chromatographies according to water/dioxanes elution
Purifying.Merge the collection liquid containing product, in -78 DEG C of freezings, freeze, obtain title compound 16 (477mg, 61% yield).
ESI MS m/z-C14H19N4O6PS2 (M-H), calculated value 433.05, finds 433.20.
Embodiment 7:3- ((double ((2- (pyridine -2- base disulphanes base) ethyl) amino) phosphoryls) amino)-propionic acid (18).
Added in THF (100ml) solution of (pyridine -2- base disulphanes base) ethylamine hydrochloride (2.10g, 11.29mmol)
Tri-chlorination phosphinylidyne (0.85g, 5.59mmol).- 78 DEG C stirring 1 it is small when after, into mixture add triethylamine (1.0g,
9.90mmol), and by resulting solution be stirred at room temperature 3 it is small when to produce double (2- (pyridine -2- base disulphanes base) ethyl)-ammonia
Base phosphinylidyne dichloro (17).Then by 3- alanines (0.61g, 6.85mmol) in THF/H2O(2:1,30ml) solvent neutralizes three
Ethamine (1.80g, 17.82mmol) is added in mixed solution.Gained mixture is stirred at 35 DEG C 3 it is small when, be concentrated in vacuo
And with H2O/CH3CN(1:20~1:10) SiO of elution2Purified on column, obtaining title compound 18, (1.47g, 63% receives
Rate).ESI MS m/z-C17H23N5O3PS (M-H), calculated value 504.05, finds 504.20.
Embodiment 8.3- ((double ((2- (pyridine -2- base disulphanes base) ethyl)-amino) phosphoryls) amino) 2,5- dioxies
For pyrrolidin-1-yl propionic ester (19).
3- ((two ((2- (pyridine -2- base disulphanes base) ethyl) amino) phosphoryls) amino) propionic acid (18) (0.52g,
NHS (0.20g, 1.74mmol) and EDC (0.80g, 4.16mmol) 1.03mmol) is added in DMA (30ml) solution.Will mixing
Thing is stirred overnight under Ar, is evaporated and in short SiO2EtOAc/CH is used in chromatography2Cl2(1:4~1:1) it is purified by flash.Merging contains
The collection liquid of product, is evaporated in vacuo, obtains title compound 19 (536mg, 79% yield).ESI MS m/z+
C21H27N6NaO5PS4(M+Na), calculated value 625.06, find 625.20.
Embodiment 9.1- (2- (methylamino) ethyl) -1H- pyrrole-2,5-diones (43)
By N at 0 DEG C1Add in DMA (150ml) solution of-methyl ethane -1,2- diamines (10.23g, 138.08mmol)
Enter succinic anhydride (13.82g, 138.08mmol).Ar stirred at 0 DEG C 1 it is small when, be then stirred at room temperature 4 it is small when, evaporation mixing
Thing, is re-dissolved in acetic acid (100ml, 98%) and Ac2In O (0.5ml), then when 80 DEG C of heating 8 are small.Concentrate mixture, with
Water/CH3The C-18 flash chromatographies of OH (100% water to 60% water containing 0.3%HCl) elution, obtain hydrochloride form
Title compound.(13.68g, yield 52%).ESI MS m/z+155.10(M+H).
Embodiment 10.3- ((double ((2- (2,5- dioxo -2,5- dihydro -1H- pyrroles -1- bases) ethyl) (methyl)-ammonia
Base) phosphoryl) (methyl) amino) propionic acid (50)
- 78 DEG C cooling 1- (2- (methylamino) ethyl) -1H- pyrroles -2,5- dione hydrochlorides (43) (4.05g,
Tri-chlorination phosphinylidyne (1.59g, 10.50mmol) is added in THF (100ml) solution 21.00mmol).When -78 DEG C of stirrings 1 are small
Afterwards, triethylamine (1.2g, 11.88mmol) is added into mixture, by resulting solution be stirred at room temperature 3 it is small when, produce double (2-
(2,5- dioxo -2,5- dihydro -1H- pyrroles -1- bases) ethyl (methyl))-amino phosphoryl chloride phosphorus oxychloride (49).Then by 3- (methyl ammonia
Base) propionic acid (1.21g, 11.73mmol) is added in the mixture of THF (30ml) and triethylamine (1.20g, 11.88mmol)
In the solution.Gained mixture is stirred at 45 DEG C 3 it is small when, be concentrated in vacuo and with H2O/CH3CN(1:20~1:10) elute
SiO2Purified on column, obtain title compound 50 (2.44g, 51% yield).ESI MS m/z-C18H25N5O7P (M-H), meter
Calculation value .454.16, finds 454.20.
Embodiment 11.3- ((double ((2- (2,5- dioxo -2,5- dihydro -1H- pyrroles -1- bases) ethyl) (methyl) amino)
Phosphoryl) (methyl) amino) 2,5- dioxo pyrrolidin -1- bases ethyl propionates (51)
NHS (0.40g, 3.48mmol) and EDC is added in compound 50 (1.10g, 2.41mmol) in DMA (40ml)
(1.80g, 9.37mmol).Mixture is stirred overnight under Ar, is evaporated and in short SiO2Acetone/CH is used in chromatographic column2Cl2(1:
6~1:2) it is purified by flash.Merge the collection liquid containing product, be evaporated in vacuo, obtain title compound 51 (971mg, yield
73%).ESI MS m/z+C22H29N6NaO9P (M+Na), calculated value 575.17, finds 575.20.
The each chain junctor of embodiment 12. has the coupling (52a) of two DM1 and antibody.
By compound 51 (20mM in the dma, 35 μ L), buffer solution (60 μ L, 100mM NaH2PO4, pH5.0~7.0) and
DM1 (20mM in the dma, 85 μ L) is when 15~30 DEG C of incubations 20 minutes~2.5 are small.Then 2.0mL is fed the mixture into
PH 6.5~8.0PBS buffer solutions of the anti-Her2 antibody of 10mg/ml, 1.0~2.0mL100mM NaH2PO4, pH7.5 buffer solutions.
By sub-titled compound solution when incubation at room temperature 2~24 is small, with 100mM NaH2PO4, the bufferings of 50mM NaCl pH 5.5~7.5
Liquid eluent purifies on G-25 columns, obtains 16.5~18.3mg compounds 52a (~86% in 11.6~14.2ml buffer solutions
Yield).Calculating DM1/ antibody ratios according to bibliography (Zhao, R.Y. et al., J.Med.Chem.2011,54,3606) is
6.8~7.8.Pass through SEC HPLC (Tosoh Bioscience, Tskgel G3000SW, 7.8mm ID x 30cm, 0.5ml/
Min, 100min) analysis be 95-99% monomers,
Alternatively, compound 51 (20mM in the dma, 35 μ L) is added to the pH 6.5 of the anti-Her2 antibody of 2.0mL 10mg/ml
The 100mM NaH of~8.0PBS buffer solutions and 0.5~1.7mL2PO4, the mixed liquor of the buffer solution of pH6.5~8.0.2h is incubated in RT
Afterwards, mixture purifies on G-25 columns, with 100mM NaH2PO4, the elution of 5.5~7.5 buffer solutions of 50mM NaCl pH.Then to
DM1 (70 μ L, 2 in the dma 20mM) and DMA (0.1~0.5ml) is added in subject's solution (4.5~6.5ml) of collection.With
Mixture is purified, with 100mM NaH when RT incubations 2-16 is small on G-25 columns afterwards2PO4, 50mM NaCl pH 5.5~
7.5 buffer solutions elute, and obtain 15.8~17.3mg compounds 52a (~81% yield) 15.5~17.4ml buffer solutions.DM1/ resists
(it is according to bibliography (Zhao, R.Y. et al., J.Med.Chem for 7.1~7.7 for body ratio.2011,54,3606) calculate).
By SEC HPLC (Tosoh Biosciences, Tskgel G3000SW, 7.8mm ID × 30cm, 0.5ml/min,
100min) analysis is 95-99% monomers.
Embodiment 13. carries the hydrophily chain junctor and the compound 147a of tubulysin analogs coupling of the present invention.
Compound 146a (Huang Y. etc. are added in THF (3.0ml) solution of compound 51 (120mg, 0.217mmol)
People, pharmaceutical chemistry the 44th, the 249th American Chemical Society's annual meeting, Denver, CO city, 22 days to 26 March in 2015
Day;World Intellectual Property Organization WIPO patent application WO2014009774) (151mg, 0.199mmol) THF (3.0ml) and buffer solution
(5ml, 100mM Na2HPO4, pH 7.2) in.Be stirred at room temperature 4 it is small when after, concentration mixture simultaneously with C-18 preparation HPLCs (grow
250mm × internal diameter 30mm) purifying, mobile phase is water/ethanol (by 90% water to 50% water, 65 ml/min of flow velocity in 35 minutes
Clock).Merge the collection component liquid containing product, concentrate simultaneously with EtOH/ hexanes crystallization, obtain title compound (159mg, 67%
Yield).ESI MS m/z+
C56H82N11NaO14PS (M+Na), calculated value 1218.35, finds 1218.40.
14. compound 147a of embodiment obtains 148a with antibody coupling.
To 2.0mL concentration for the anti-Her2 antibody (pH6.0~8.0) of 10mg/ml mixture in add 0.70~
2.0mLPBS buffer solutions (100mM NaH2PO4, pH 6.5~7.5), TCEP (28 μ L, 20mM aqueous solution) and compound 147a
(35 μ L, 20mM is in DMA).By mixture when RT incubations 2-16 is small, DHAA (135 μ L, 50mM) is then added.At room temperature
After being continuously incubated overnight, by mixture 100mM NaH2PO4, 50mM NaCl, the buffer solution of pH6.0~7.5 is as eluent
Purified on G-25 columns, obtain 16.8~17.9mg in 13.1~14.9ml buffer solutions coupling compounds 148a (~
87% yield).It is 2.8~3.7 through UPLC-Qtof mass spectroscopies medicine/antibody ratio (DAR).Pass through SEC HPLC (Tosoh
Biosciences, Tskgel G3000SW, 7.8mm ID x 30cm, 0.5ml/min, 100min) analysis for 96-99% it is mono-
Body, and single band is measured as by PAGE gel.
In addition test, the anti-Her2 antibody of the 10mg/ml for the 2.0mL in PBS buffer for being 6.0~8.0 by pH,
PH6.0~8.0,100mM NaH2PO40.50~1.5mL of buffer solution, and DTT (aqueous solutions of 30 μ L, 20mM) is 15~37
DEG C be incubated 1~5h, then with 100mM NaH2PO4, 50mM NaCl, the buffer solutions of pH6.0~8.0 is as eluent in G-25 columns
Upper purifying.The collection component liquid (3.8-5.8ml) containing product will be merged and add 0.2-0.6mL DMA and compound 147a (35 μ
The DMA solution of L, 20mM), when incubation 4-12 is small under RT.Add DHAA (135 μ L, 50mM) and be continuously incubated overnight under RT
Afterwards, mixture is purified on G-25 columns, with 100mM NaH2PO4, the elution of 50mM NaCl pH7.5 buffer solutions, obtain 15.5~
13.8~15.9ml buffer solutions of 16.8mg combination compounds 148a (~80% yield).Pass through UPLC-QTOF mass spectroscopies
Medicine/antibody ratio (DAR) is 2.6~3.8.By SEC HPLC (Tosoh Biosciences, Tskgel G3000SW, 7.8mm
ID × 30cm, 0.5ml/min, 100min) analysis is 96-98% monomers, and measures single bands of a spectrum by PAGE gel.
The vitro cytotoxicity assessment of embodiment 15. conjugate 52a and 148a:
Target cell (such as N-87, SKOV3 and HL60 cells, 6000 cells) is even in the anti-Her2 antibody of various concentrations
When culture 96 is small in the presence of connection thing 52a and 148a, then using Becton Dickinson FACSort (Becton
Dickinson, Franklin Lakes, NJ) flow cytometer pass through propidium iodide exclusion measure cell viability.The cell of excitation
Red fluorescence intensity (in FL2 passages 617nm launch) measured under 488nm.In addition the positive light scattering of cell is used
The region of living cells is set with right angle light scatter property.The forfeiture of living cells is thin in the gated regions by definition survivaling cell
What the loss of born of the same parents determined.Average viable count is calculated by every 6 repetition cultures and obtained.CNN surviving fraction is drawn to conjugate concentration
To determine the IC of conjugate 52a and 148a50Value (50% cell kills concentration).
Cytotoxicity result:
Conjugate 52a is to the specificity of N87 cells more than 1850 (IC50>50/IC50=0.027), to SK-OV-3 cells
More than 2380.
Conjugate 148a is to the specificity of N87 cells more than 1315 (IC50>50/IC50=0.038), it is thin to SK-OV-3
Born of the same parents are more than 1560.
Conjugate 52a and conjugate 148a is unusual high activity and positive with very specific targeting antigen
Tumour cell.
Claims (31)
1. the hydrophily linking group compound of formula (I):
Wherein:
Y represents the functional group that can be reacted with cell binding agent, and Y is selected from mercaptan, disulphide substituent, dimaleoyl imino,
Haloacetyl, alkynyl, alkoxy amino, carboxylic acid, carboxylic acid halide, nitro phenyl ester, dinitro phenyl ester, trifluoro-benzene base ester or N-
Hydroxysuccinimide eater;
Q and T is-X1- P (=O) (OM)-, or-X1-S(O2)-, or-X1–S(O)-;Or-X1- P (=O) (OM)-X2-, or-X1–P
(=O) [X2-R4-Z]-X3-, or-X1- P (=O) [X2-R1-Y]-X3-, or-X1-S(O2)-X2-, or-X1–S(O)-X2-;
X1,X2And X3Independently selected from N (R7), O, or S;In addition, work as X1It is N (R7), or during O or S, then X2Or X3Or another X1
With-P (=O) ,-S (O), or-S (O2) connection when, X2Or X3Or another X1Can be CH2;
M and n is the integer from 0 to 5, but cannot be 0 at the same time;
Z represents a functional group, can be by thio, thioesters, peptide, hydrazone, ether, ester, carbamate, carbonic ester, amine (two
Level, three-level or level Four), imines, cycloheteroalkyl, heteroaromatic group, one cytotoxic drug of alkane oxime or acid amides key connection;
R1,R2,R3,R4,R5,R6, and R7It is, it is identical or different, it is H, the straight chained alkyl with 1-6 carbon atom, has 3-6
The side chain or cyclic alkyl of carbon atom, straight chain, side chain or cyclic alkenyl or alkynyl, ester, ether, the acid amides of 1-6 carbon atom, or
Molecular formula is (OCH2CH2)p, polyethyleneoxy unit, wherein p are the integers of 0 to about 1000, or combinations thereof;
M is H, or Na, or K, or N+R1R2R3Or pharmaceutical salts.Above to R1,R2And R3It is described.
2. cell-binding molecules-drug conjugate compound of formula (II):
Wherein:
Cb represents cell binding agent/molecule;
" Drug " refer to alkyl, alkylidene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imines, polyamines, hydrazine, hydrazone,
Acid amides, urea, semicarbazides, carbonohydrazides, alkoxyamine, aminocarboxylic acid ester, amino acid, peptide, acyloxy amine, hydroxamic acid, two sulphur
Compound, thioether, thioesters, carbamate, carbonic ester, heterocycle, miscellaneous alkyl, heteroaromatic or alkane oxime key or its combinations thereof group lead to
Cross the medicine that hydrophilic linkers are connected with cell binding agent;
Q is 1~30;
Wherein Q, T, m, n, R1,R2,R3,R4,R5, and R6Define identical with the definition in claim 1.
3. the compound of formula (III):
Wherein:
Q, T, Z, m, n, R1,R2,R3,R4,R5, and R6Define identical with the definition in claim 1;
The definition of Cb and q is identical with claim 2.
4. the compound of formula (IV):
Wherein:
Y, Q, T, m, n, R1,R2,R3,R4,R5, and R6Definition is identical with the definition in claim 1,
The definition of Drug is identical with claim 2.
5. formula (I) compound of claim 1, wherein Q or/and T are-X1- P (=O) [X1-R1-Y]-X3-, therefore formula (I) chemical combination
Thing can be used for connecting two or more sites, or the position of a pair of of cell-binding molecules comprising two or more Y groups
Point;
X therein1,X2And X3Independently selected from N (R7),O,CH2, or S;Y,R1And R7As defined in claim 1.
6. formula (I) compound of claim 1, wherein Q or/and T are-X1- P (=O) [X2-R4-Z]-X3-, therefore formula (I) chemical combination
Thing can be used for connecting two or more medicines comprising two or more Z groups;
X therein1,X2And X3Independently selected from N (R7),O,CH2, or S;Z,R4And R7As defined in claim 1.
7. formula (II) coupling compound of claim 2, wherein Q or/and T are-X1- P (=O) [X1-R1-Cb]-X3-, therefore formula
(II) compound connects two or more sites, or the position of a pair of of cell-binding molecules comprising two or more Cb groups
Point;
X therein1,X2And X3Independently selected from N (R7),O,CH2, or S;Y,R1And R7As defined in claim 1;Cb is defined such as
Defined in claim 2.
8. formula (II) coupling compound of claim 2, wherein Q or/and T are-X1- P (=O) [X2-R4-Drug]-X3-, therefore
Formula (II) compound connects two or more identical or different medicines comprising two or more " Drug ";
X therein1,X2And X3Independently selected from N (R7),O,CH2, or S;Y,R4And R7As defined in claim 1;" Drug " is fixed
Justice is as defined in claim 2.
9. formula (III) compound of claim 3, wherein Q or/and T are-X1- P (=O) [X2-R1-Cb]-X3-, therefore formula
(III) compound includes two or more Cb groups and connects two or more sites, or a pair of of cell-binding molecules
Site;
X therein1,X2And X3Independently selected from N (R7),O,CH2, or S;R1And R7As defined in claim 1;Cb definition as
Defined in claim 2.
10. formula (III) compound of claim 3, wherein Q or/and T are T is-X1- P (=O) [X2-R4-Z]-X3-, therefore formula
(III) compound can be used for connecting two or more identical or different medicines comprising two or more Z groups;
X therein1,X2And X3Independently selected from N (R7),O,CH2, or S;R4And R7As defined in claim 1.
11. formula (IV) compound of claim 4, wherein Q or/and T are-X1- P (=O) [X2-R1-Y]-X3-, therefore formula (IV)
Compound can be used for connecting two or more sites, or a pair of of cell-binding molecules comprising two or more Y groups
Site;
X therein1,X2And X3Independently selected from N (R7),O,CH2, or S;R1And R7As defined in claim 1.
12. formula (IV) compound of claim 4, wherein Q or/and T are-X1- P (=O) [X2-R4-Drug]-X3-, therefore formula
(IV) compound connects two or more identical or different medicines comprising two or more " Drug ";
X therein1,X2And X3Independently selected from N (R7),O,CH2, or S;Y,R4And R7As defined in claim 1;" Drug " is fixed
Justice is as defined in claim 2.
13. according to claim 2,4,8 or 12 compound, wherein " Drug " is selected from:
1) chemotherapeutics:
A) alkylating reagents:Chlorambucil, chlorine naphazoline, endoxan, Dacarbazine, Estramustine, different ring phosphinylidyne
Amine, mustargen, Mechlorethaminoxide Hydrochloride, mannomustin, dibromannitol, melphalan, mitolactol, pipobroman, novembichin,
Phenesterin, pennisetum mustard, thiotepa, trofosfamide, uracil mastard;CC-1065 and its Ah more carry out star, card folding carrys out star,
Carry out star synthetic analogues than rolling over;Times carcinomycin and its synthetic analogues KW-2189 and CBI-TMI;Pyrrolo- Benzodiazepine, holds in the palm horse
The dimer of mycin, indoline and Benzodiazepine, imidazo Benzodiazepine or oxazolidine and Benzodiazepine;Carmustine, Lip river is not
Take charge of spit of fland, chloramphenicol, Fotemustine, Nimustine, Ranimustine;Busulfan, treosulfan, Improsulfan and A-20968;Dacca
Bar piperazine;Carboplatin, cis-platinum, oxaliplatin;Benzodepa, carboquone, Meturedepa and uredepa;Hemel, three ethylenes honey
Amine, triethylene glycol phosphamide, triethyl group thio-phosphamide and trimethylol melamine;
B) plant alkaloids:Vincristine, vincaleukoblastinum, eldisine, vinorelbine, vinorelbine;Taxol, more west are purple
China fir alcohol and the like, maytansinoid and the like, cryptophycin 1 and cryptophycin 8;Epothilones, Eleutherobin,
Circle suberite lactone, bryostatins, his fourth of more Rosss, Ali's statin, tubulysins, Cephalostatins;Water ghost any of several broadleaf plants alkali;
Coral element A;spongistatin;
C) .DNA topoisomerase enzyme inhibitors:9-aminocamptothecin, camptothecine, crisnatol, daunorubicin, Etoposide, phosphorus
Sour Etoposide, Irinotecan, mitoxantrone, mitoxantrone hydrochloride, retinoic acid, retinol, Teniposide, topotecan, 9-
Nitrocamptothecin;Mitomycin C;
D) antimetabolites:Methotrexate, Trimetrexate, denopterin, pteropterin, aminopterin or other folacins;
Mycophenolic acid, formamido thiazole, Ribavirin, EICAR;Hydroxycarbamide, Deferoxamine;Ancitabine, azacitidine, 6-aza uridine,
Capecitabine, Carmofur, cytarabine, di-deoxyuridine, doxifluridine, Enocitabine, 5 FU 5 fluorouracil, floxuridine, La Tai
Qu Ke;Cytarabine, cytarabin, fludarabine;Imuran, fludarabine, purinethol, imuran
Amine, thioguanine;Folinic acid;
E) hormonotherapies:Megestrol acetate, Raloxifene, tamoxifen;Goserelin, leuprorelin acetate;Bicalutamide, fluorine
His amine, clausterone, dromostanolone propionate, epithio, Goserelin, leuprorelin acetate, Mepitiostane, Nilutamide and Qu Luosi
It is smooth;CB1093, EB1089KH1060, Vitamin D3, calciferol;Verteporfin, phthalocyanine, photosensitizer PC4, de-methoxy bamboo are red
Fungus beetle element;Alpha-interferon, chronic bronchitis tumor necrosis factor, the protein domain containing TNF of the mankind;
F) kinase inhibitors:Bibw2992, Imatinib, Gefitinib, piperazine Jia Tani, Sorafenib, Dasatinib, Shu Ni
It is general for Buddhist nun, Tarceva, nilotinib, Lapatinib, Axitinib, pazopanib, Vande Thani, e7080, Mubritinib
Receiving and replace Buddhist nun, Ba Fei replaces Buddhist nun, posupini, and card is rich to replace Buddhist nun, vismodegib, Iniparib, star bright Ai Ke, CYT387, Axitinib,
Filled in for Fu Zhani, bevacizumab, Sorafenib, Herceptin, Cetuximab, ranibizumab, Victibix, her Buddhist nun;
G) antibiotic:Calicheamycin, calicheamicin γ 1, δ 1, α 1 and β 1, dynemicin A and deoxydynemicin,
Esperamicin, Kedarcidin, C-1027, maduropeptin, and neocarzinostatin chromophore and its corresponding chromoprotein
Enediyne Antibiotic chromomophores, aclacinomysins, D actinomycin D, authramycin, azaserine,
Bleomycin A5, act-C, carabicin, carminomycin, carzinophillin;Chromomycin, dactinomycin D, daunomycin, ground Toby
Star, 6- diazonium -5- oxn-l-norieucins, adriamycin, morpholine adriamycin, cyano group morpholine adriamycin, 2- pyrrolinodoxorubicins and
Deoxygenate adriamycin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olive
Olive mycin, Peplomycin, potfiromycin, puromycin, triferricdoxorubicin, rodorubicin, streptonigrin, streptozotocin,
Tubercidin, ubenimex, Zinostatin, zorubicin;
H) other:Its octanone of its pungent and Bradley of Bradley;Gemcitabine, Ka Feizuo meter, bortezomib, Thalidomide,
Lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-9090, Stimuvax,
Allovectin-7, Xegeva, Provenge, Yervoy, Lovastatin, 1-methyl-4-phenylpyridinium ion, star spore bacterium
Element, actinomycin D, D actinomycin D, bleomycin Bleornycin A2, B2, Peplomycin, daunorubicin, adriamycin, she reach than
Star, Epi-ADM, pirarubicin, daunorubicin, mtoxantrone, Verapamil, thapsigargin, vorinostat,
Romidepsin, pabishta, valproic acid, mocetinostat, belinostat, PCI-24781, entinostat, SB939,
Resminostat, givinostat, AR-42, CUDC-10, sulforaphen, Trichostatin A;Celecoxib, glitazone, table
Nutgall catechin gallic acid ester, disulfiram, salinosporamide A.;Aminoglutethimide, mitotane, Trilostane;Acyl
Glucurolactone;Aldophosphamideglycoside;Aminolevulinic acid;Amsacrine;Cytarabine bestrabucil;Bisantrene edatraxate;
defofamine;Colchicin;Phenodiazine compound;Eflornithine, elfomithine;Elliptinium Acetate, etoglucid;Nitric acid
Gallium;Gacytosine, hydroxycarbamide;Ibandronate, lentinan;Lonidamine;Methyl-GAG;Mitoxantrone;Mopidamol;
nitracrine;Pentostatin;Phenamet;Pirarubicin;Podophyllic acid;Ethyl hydrazine;Procarbazine;Tetrahydroform;Nitragin;West
Assistant is muttered;Spirogermanium;Tenuazonic acid;Triaziquone;2,2 ' 2 "-trichlorotriethylamine;T-2 toxin, single-ended sp, wart
Spore rhzomorph A, Roridine A and anguidine;Urethane, interference micro ribonucleic acid (siRNA), antisense drug;
2) the anti-autoimmune disease medicines of:Cyclosporine, ciclosporin A, aminocaproic acid, imuran, bromocriptine, benzenebutanoic acid nitrogen
Mustard, chloroquine, endoxan, Amcinonide, betamethasone, budesonide, hydrocortisone, flunisolide, fluticasone propionate,
Fluocortolone, danazol, dexamethasone, Triamcinolone acetonide, beclomeasone propionate, dehydrobenzene, Etanercept, hydroxychloroquine, Ying Fu
Sharp former times monoclonal antibody, Meloxicam, methotrexate (MTX), learn, mycophenolate, metacortandracin, sirolimus, tacrolimus;
3) anti-infectious diseases medicine:
A) aminoglycosides:Amikacin, azithromycin, Netilmicin, sisomicin, Isepamicin, hygromycin B, butylamine card
That mycin, Arbekacin, kanamycin B, dibekacin, tobramycin, actiline, paromomycin, ribostamycin, how for rice
Star, spectinomycin, streptomysin, tobramycin, Weida's rice star;
B) chloromycetin series antibioticses class:Azidamfenicol, chloramphenicol, Florfenicol, Thiamphenicol;
C) Ansamycins class:Geldanamycin, herbimycin;
D) carbapenem antibiotics class:Biapenem, donipenem, ertapenem, Imipenem, cilastatin, Metro training
South, Panipenem;
E) cephalo-types:Carbacephem, Cefacetrile, Cefaclor, Cefradine, cefadroxil, cefalonium, cefaloridine,
Cephalothin or cefoxitin, cefalexin, cefaloglycin, cefadole, cefapirin, cefatrizine, Cefazaflur, head
Cefazedone, cephazoline, cefbuperazone, Cefcapene, Cefdaloxime, Cefepime, Cefminox, Cefoxitin, cephalo third
Alkene, cefroxadine, ceftezole, cefuroxime, Cefixime Cefdinir, cefoperon, cefetamet, Cefmenoxime, head
Spore ground piperazine, cefonicid, cefoperazone, ceforanide, cefotaxime, Cefotiam, Cefozopran, Cefpimizole, cephalo
Amine, Cefpirome Cefpodoxime, Cefquinome, Cefsulodin, cefotaxime, Cefteram, Ceftibuten, Ceftiolene, head
Spore azoles oxime, Ceftobiprole, ceftriaxone, cefuzonam, Cefoxitin, cefotetan, cefmetazole, Flomoxef, draws oxygen head
Spore;
F) glycopeptides class:Bleomycin, oritavancin, Te Lawan stars, teicoplanin, Ramoplanin;
G) glycyl ring class:Tigecycline;
H) beta-lactamase inhibitors class:Penam, Sulbactam, Tazobactam Sodium, clavulanic acid;
I) LIN Keshengs:Clindamycin, lincomycin;
J) lipopeptids:Daptomycin, A54145, Ca-dependent antibiotic;
K) macrolide antibiotics:Erythromycin, azithromycin, clarithromycin, Dirithromycin, erythromycin, roxithromycin, is handed over
Arenomycin, Ketek, cethromycin, medecamycin, methomycin, oleandomycin, rifampin, Mycobutin, Rifapentine,
Rokitamycin, roxithromycin, spectinomycin, spiramvcin, tacrolimus, troleandomycin, Ketek;
L) monobactamses:Aztreonam, Tigemonam;
M) oxazolidinones:Linezolid;
N) penicillin antibiotics:Amoxicillin, Pivampicillin, hetacillin, Bacampicillin, metampicillin, Talampicillin,
Azidocillin, azlocillin, benzyl penicillin, tardocillin, tardocillin, Benzathine Phenoxymethylpenicillin, clometocillin,
Procaine benzylpenicillinate, carbenicillin, Cloxacillin, dicloxacillin, Epicillin, flucloxacillin, Mecillinam, Mei Luoxi
Woods, methicillin, naphthlazole, oxacillin, penamecillin, penicillin, pheneticillin, ospen, Piperacillin, third
XiLin, sulbenicillin, temocillin, Ticarcillin;
O) polypeptides:Bacitracin, colistin, polymyxin B;
P) quinolones:Alafloxacin, Balofloxacin, Ciprofloxacin, Clinafloxacin, Enoxacin, Enrofloxacin are husky up to fluorine
Star, Difloxacin, Ofloxacin, T-3811, gatifloxacin, gemifloxacin, Grepafloxacin, Kano trovafloxacin, left oxygen fluorine
Sha Xing, Lomefloxacin, marbofloxacin, Nadifloxacin, Moxifloxacin, Orbifloxacin, Norfloxacin, Ofloxacin, Pefloxacin,
Trovafloxacin, sitafloxacin, Sparfloxacin, Grepafloxacin, Temafloxacin, Tosufloxacin, trovafloxacin;
Q) sun bacteriums:Pristinamycin, Quinupristin, Dalfopristin
R) sulfamidos:Mafenide, prontosil, sulfacetamide, sulfamethizole, salicylazosulfapyridine, bacteresulf,
Trimethoprim, sulfamethoxazole;
S) steroids antimicrobial:Fusidic Acid;
T) tetracycline antibiotics:Doxycycline, chlorine hydroxytetracycline, duomycin, lymecycline, demethylchlortetra cylinum, soil are mould
Element, minocycline, chloromethoxazole, oxytetracycline, penimepicycline, bristacin, tetracycline, tigecycline;
U) antibiotic of others type:Annonacin, Arsphenamine, bacitracin, seromycin, circle suberite lactone, end pomegranate
It is plain to fill in Lip river, Epothilones, ethambutol, Etoposide, faropenem, Fusidic Acid, furazolidone, isoniazid,
Laulimalide, metronidazole, mupirocin, bacterial lactone, phosphonomycin, Nitrofurantoin, taxol, tablet mycin, pyrazine
Acid amides, Quinupristin/Dalfopristin, rifampin, Tazobactam Sodium fasigyne, Annona lactone;
4) antiviral drugs:
A) inputs/fusion inhibitor:A Pula Wei sieve, maraviro, vicriviroc, T-20, PRO140, according to Barry
Sufficient monoclonal antibody ibalizumab;
B) integrase inhibitors:Merck, angstrom for draw Wei, globoidnanA;
C) maturations inhibitor:Bevirimat, vivecon;
D) neuraminidase inhibitors:Oseltamivir, zanamivir, Peramivir;
E) nucleosides and nucleotide:Abacavir, acyclovir, Aldoforwe ester, amdoxovir, his shore of A Purui west, bromine husband
It is fixed, cidofovir, right Elvucitabine, Clevudine, Didanosine, Elvucitabine, emtricitabine, Entecavir, famciclovir,
Fluorouracil, 3 '-fluoro- 2 ', 3 '-Didansine, 3 '-fluoro- 2 ', 3 '-dideoxyguanosine, Fomivirsen, Ganciclovir, blister
Rash is net, Lamivudine, β -1- thymidines and β -1-2 '-deoxycytidine, Penciclovir, racivir, Ribavirin, stampidine,
Stavudine, taribavirin, Sebivo, tenofovir, three Valaciclovirs, valganciclovir, zalcitabine, Qi Duofu
It is fixed;
F) non-nucleosides medicine:Amantadine, ateviridine, capravirine, etravirine, rilpivirine, Delavirdine,
22 alcohol, emivirine, efavirenz, phosphonic acid, imiquimod ,-interferon, Loviride, lodenosine, methisazone,
Nevirapine, NOV-205, Peg-IFN alpha-2b, podophyllinic acid lactone, rifampin, rimantadine, resiquimod;
G) protease inhibitors:Anpunave, atazanavir, Bo Saipowei, darunavir, fosamprenavir, indinavir, Lip river
That Wei, Nai Feinawei, Ritonavir, pula Sean Connery, inverase, telavi, tipranavir;
H) other types antiviral drugs:Abzyme, Abiduoer, poon lactone A, ceragenin, blue algae antiviral protein
N, Diarylmiazines compound, Epigallo-catechin gallate (EGCG), phosphonic acid, griffithsin, Ta Liweilin, hydroxyl
Base urea, KP-1461, Miltefosine, pula Sean Connery, Ribavirin, Seliciclib.
5) radio isotopes can be selected from (radionuclide)3H,11C,14C,18F,32P,35S,64Cu,68Ga,86Y,99Tc,111In,123I,124I,125I,131I,133Xe,177Lu,211At, or213Bi.
6) chromophore molecules:Selected from ultraviolet light, fluorescent lamp, infrared light, near infrared light, visible ray, one or more uranidin,
Red blood cell, iridescent colors, procrypsis, melanin, cyano group, fluorescent chemicals, light shine, are visual light transduction molecule, light emitting molecule, glimmering again
Light element compound;Nonprotein organic fluorescence group is selected from:Yellow, red cell body, cell color, leucocyte, mel-
Anophores, cyano group group, fluorescent chemicals fluorescent chemicals, light shine again, visual light transduction molecule, illuminophore molecule, shine
Molecule, Fluorescein compound;Xanthene derivative (fluorescein, rhodamine, Oregon is green, eosin and texas Red);Hua Jing
Derivative (Hua Jing, indoles carbocyanine, oxa- cyanine, thiocyanine and portion spend cyanines);Side's acid cyanines derivative and cyclosubstituted side acid
Cyanines (including Seta, SeTau and Square dyestuffs);Naphthalene derivatives (dansyl and prodan derivatives);Coumarin derivative;Dislike two
Zole derivatives (pyrido oxazole, nitrobenzoxadiazole and benzoxadiazole);Anthracene derivant (Anthraquinones, including DRAQ5,
DRAQ7 and CyTRAK oranges);Pyrene derivatives (cascade blueness);Oxazines derivative (Nile red, Nile blue, cresol-purple, oxazines 170);
Acridine derivatives (proflavin flavine, acridine orange, acridine yellow);Arylmethylamine derivative (auramine, crystal violet, malachite
It is green);Tetrapyrrole derivative (porphines, phthalocyanine, bilirubin);Any analogs and derivatives of following fluorophore compounds:CF contaminates
Expect (Biotium), DRAQ and CyTRAK probes, BODIPY, Alexa Fluor, DyLight Fluor, Atto and Tracy
Ab), DY and MegaStokes Dyes, Sulfo Cy dyestuffs (Cyandye), HiLyte Fluor, Se-ta, SeTau and
Square Dyes (SETA BioMedicals), Quasar (APC), APC, APCXL, RPE, BPE (algae bio technology), not
Phycocyanin (APC), aminocoumarin, APC-Cy7 conjugates, BODIPY-FL, Cascade Blue, Cy2, Cy3, Cy3.5,
Cy3B, Cy5, Cy5.5, Cy7, Fluoresce-in, FluorX, Hydroxycoumarin, Sulforhodamine B, lucifer yellow,
Methoxycoumarin, NBD, the Pacific Ocean is blue, Pacific Ocean orange, PE-Cy5 conjugates, PE-Cy7 conjugates, PerCP, R- algae reds
Albumen (PE), Red 613, Seta-555- nitrine, Seta-555-DBCO, Seta-555-N- HOSu NHSs, Seta-
580-N- HOSu NHSs, Seta-680-N- HOSu NHSs, Seta-780-N- HOSu NHSs,
Seta--APC-780, Seta-PerCP-680, Seta-R-PE-670, SeTau-380-N- HOSu NHS, SeTau-
405- maleimides, SeTau-405-N- HOSu NHSs, SeTau-425-N- HOSu NHSs, SeTau-
647-N- HOSu NHSs, Texas Red, TRITC, TruRed, X- rhodamines, 7-AAD (7-aminoactinomycin D,
CG- selectivity), acridine orange, ChromomycinA3, CyTRAK orange (Biostatus, red excitation are black), DAPI, DRAQ5,
DRAQ7, ethidium bromide, Hoechst33258, Hoechst33342, LDS751, Mith- thunder mycins, propidium iodide (PI),
SYTOX is blue, SYTOXGreen, SYTOX orange, thiazole Or-ange, TO-PRO:Cyanine monomer, TOTO-1, TO-PRO-1, TOTO-
3, TO-PRO-3, YOSeta-1, YOYO-1.Can be with the fluorogen chemical combination for being used to study the connexon of cell and being connected of the present invention
Thing is selected from following compounds or derivatives thereof:DCFH (2'7'Dichorodihydro-fluorescein, oxidised form), DHR
(dihydro Rhodamine 123, oxidised form, light cat agent oxidation), Fluo-3 (AM esters, pH>6), Fluo-4 (AM esters, pH7.2),
Indo-1 (AM esters, low high calcium (Ca 2+)), SNARF (pH 6/9) allophycocyanin (APC), AmCyan1 (tetramer,
Clontech), AsRed2 (tetramer, Clontech), Azami Green (single aggressiveness, MBL), Azurite, B-
phycoerythrin(BPE),Cerulean,CyPet,DsRed monomer(Clontech),DsRed2("RFP",
Clontech), EBFP, EBFP2, ECFP, EGFP (weak dimer, Clontech), Emerald companies (Emerald companies), firefly
Light element B (phycoerythrin) weak dimer, Invitrogen), EYFP (weak dimer, Clontech), green fluorescent protein (S65A
Mutation), green fluorescent protein (S65C mutation), green fluorescent protein (S65L mutation), green fluorescent protein (S65T mutation) is green
Color fluorescin (Y66F mutation), green fluorescent protein (Y66H mutation), green fluorescent protein (Y66W mutation), green fluorescence egg
White uv, HcRed1, J-Red, Ka Tusha, card figure husky of common dye (monomer, MBL), mCFP, mCherry, mCitrine, Midoriishi
Cyan (dimer, MBL), mKate (TagFP635, monomer, Evrogen), mKeima-Red (monomer, MBL), mKO,
MOrange, mPlum, mRaspberry, mRFP1 (monomer, Tsien laboratories), mStrawberry, mTFP1,
MTurquoise2, P3 (phycobilisome complex), Peridinin chlorophyll (PerCP), R-PE (RPE), T-
Sapphire, TagCFP (dimer, Evrogen), TagGFP (dimer, Evrogen), TagRFP (dimer,
Evrogen), TagYFP (dimer, Evrogen), tdTomato (series connection dimer), Topaz, TurboFP602 (dimer,
Evrogen), TurboFP635 (dimer, Evrogen), TurboGFP (dimer, Evrogen), TurboRFP (dimer,
Evrogen), TurboYFP (dimer, Evrogen), Venus, wild type GFP, YPet, ZsGreen1 (tetramer,
Clontech), ZsYellow1 (tetramer, Clontech)
7) pharmaceutically acceptable salt of any of the above described medicines of, acid or derivative.
14.T such as claims 2, the compound described in 4,8 or 12, wherein when " Drug " is chromophore molecule, for detecting, supervising
Survey or study the interaction between cell-binding molecules, and/or conjugate and target or target cell or function.
15. claim 2,4,8 or 12 compound, wherein " medicine " is selected from tubulysins, Cali's miramycin, Ao Ruisita
Spit of fland, maytansine, CC-1065 derivatives, adriamycin, taxol, Epothilones and Benzodiazepine dimer, pyrroles's Benzodiazepine
Dimer, tomaymycin dimer, Anthramycin dimer, indoline Benzodiazepine dimer, imidazoles Benzodiazepine dimer,
Oxazoline Benzodiazepine dimer, siRNA or its combination, and/or the pharmaceutically acceptable salt of the above-mentioned molecule of any type, acid
Or derivative.
16. claim 2,3,7 or 9 compound, wherein the cell binding agent/molecule is selected from antibody, protein, vitamin
(folic acid), peptide, polymer micelle, liposome, the pharmaceutical carrier based on lipoprotein, nanoparticulate drug carrier, dendroid polymerization
Thing and a kind of any of the above described combination.
17. according to claim 2, cell-binding molecules/medicament any one of 3,7,9 or 16 is single-stranded selected from for antibody
Antibody, the antibody fragment combined with target cell, monoclonal antibody, single monoclonal antibodies or the monoclonal combined with target cell resist
Body fragment, chimeric antibody, the chimeric antibody fragment combined with target cell, domain antibodies, with reference to the domain antibodies of target cell
The antibody fragment of fragment, resurfaced antibody, the single-chain antibody of surface reconstruction or the surface reconstruction combined with target cell, humanization
Antibody or resurfaced antibody, Humanized single chain antibody or the humanized antibody fragment for combining target cell, lymphokine, dimension life
Element, growth factor, colony stimulating factor or Nutrient transport molecule.
18. cell-binding molecules/medicament according to any one of claim 2,3,7,9 or 16 can be directed to swell
Oncocyte, the cell of virus infection, the cell of microorganism infection, the cell of parasitic infection, autoimmune disease cell, activation
Tumour cell, bone marrow cell, the T cell of activation, infects B cell or melanocyte.
19. cell-binding molecules/agent according to any one of claim 2,3,7,9 or 16 can be can be directed to it is following
Any molecule of any antigen or acceptor:CD3,CD4,CD5,CD6,CD7,CD8,CD9,CD10,CD11a,CD11b,
CD11c,CD12w,CD14,CD15,CD16,CDw17,CD18,CD19,CD20,CD21,CD22,CD23,CD24,CD25,
CD26,CD27,CD28,CD29,CD30,CD31,CD32,CD33,CD34,CD35,CD36,CD37,CD38,CD39,CD40,
CD41,CD42,CD43,CD44,CD45,CD46,CD47,CD48,CD49b,CD49c,CD51,CD52,CD53,CD54,CD55,
CD56,CD58,CD59,CD61,CD62E,CD62L,CD62P,CD63,CD66,CD68,CD69,CD70,CD72,CD74,
CD79,CD79a,CD79b,CD80,CD81,CD82,CD83,CD86,CD87,CD88,CD89,CD90,CD91,CD95,CD96,
CD98,CD100,CD103,CD105,CD106,CD109,CD117,CD120,CD125,CD126,CD127,CD133,CD134,
CD135,CD138,CD141,CD142,CD143,CD144,CD147,CD151,CD147,CD152,CD154,CD156,
CD158,CD163,CD166,.CD168,CD174,CD180,CD184,CDw186,CD194,CD195,CD200,CD200a,
CD200b,CD209,CD221,CD227,CD235a,CD240,CD262,CD271,CD274,CD276(B7-H3),CD303,
CD304, CD309, CD326,4-1BB, 5AC, 5T4 (trophoderm glycoprotein, TPBG, 5T4, Wnt signals activation inhibiting factor 1 or
WAIF1), gland cancer antigen, AGS-5, AGS-22M6, activin receptor sample kinases 1, AFP, AKAP-4, ALK, Alpha's integrin,
Alpha v beta6, aminopeptidase N, amyloid beta, androgen receptor, angiopoietin 2, angiogenin 3, film connection egg
White A1, the protective antigens of anthrax toxin, anti-transferrin receptor, AOC3 (VAP-1), B7-H3, Bacillus anthracis anthrax,
BAFF (B- cell activation factors), B lymphoma cells, BCR-ABL, Magainin, BORIS, C5, C242 antigens, CA125 (carbon water
Compound antigen 125, MUC16), CAIX (or CAIX, carbonic anhydrase 9), CALLA, CanAg's, wolf familial IL31, carbonic anhydride
Enzyme IX, cardiac myosin CCL11 (CC motifs chemotactic factor (CF) 11), CCR4 (4 type of CC-chemokine receptor, CD194), CCR5,
CD3E (ε), CEA (carcinomebryonic antigen), CEACAM3, CEACAM5 (carcinomebryonic antigen) CFD (factor D), Ch4D5, cholecystokinin 2
(CCK2R), CLDN18 (claudin -18), coagulation factor A, CRIPTO, FCSF1R (colony-stimulating factor 1 acceptor, CD115),
CSF2 (colony stimulating factor 2, granulocyte macrophage colony stimulating factor (GM-CSF)), (cytotoxic T is thin by CTLA4
Born of the same parents' GAP-associated protein GAP 4), CTAA16.88 tumour antigens, CXCR4 (CD184), CXC chemistry-CYP1B1, cytomegalovirus, giant cell
Viral glycoprotein B, dabigatran, DLL3 (δ-sample ligand 3), DPP4-1, the type of colon bacillus shiga toxin -2, ED-B, EGFL7
(EGF spline structures domain albumen 7), EGFR, EGFRII, EGFRvIII, Endoglin (CD105), Endothelin B receptor, endotoxin,
EpCAM (Epithelial Cell Adhesion EphA2, Episialin, ERBB2 (epidermal growth factor acceptor 2), ERBB3, ERG
(TMPRSS2ETS fusions), Escherichia coli, ETV6-AML, FAP (fibroblast activation protein alpha), FCGR1, α-tire egg
In vain, β chains, fibronectin extra domain-B, FOLR (folacin receptor), folacin receptor α, folic acid hydrolase, Fos related antigens
Respiratory system ribosomes GM1, the GD2 gangliosides of 1.F albumen, G-28 (cell surface antigen glyvolipid), GD3 are unique
Type, GloboH, glypican-3, NeuGc ALPHA2-3Gal, GM3, GMCSF receptor alpha chains, growth and differentiation factor
8, GP100, GPNMB (transmembrane glycoprotein NMB), GUCY2C (guanylate cyclase 2C, guanosine cyclic mono-phosphate (GC-C), enteron aisle bird
Thuja acid cyclase, guanylate cyclase-C acceptors, Thermostable α-amylase acceptor (hSTAR)), heat shock protein, hemagglutinin, hepatitis
B surface antigen, hepatitis type B virus, HER1 (human epidermal growth factor acceptor 1), HER2, HER2/neu, HER3 (ERBB-3),
IgG4, HGF/SF (hepatocyte growth factor/dispersion factor), HHGFR, HIV-1, histone complexes, HLA-DR (human leukocytes
Antigen), HLA-DR10, HLA-DRB, HMWMAA, human chorionic gonadotrophin, HNGF, people's dispersion factor receptor kinase, HPV
The catalytic subunit of E6/E7, Hsp90, ICAM-1 (Intercellular Adhesion Molecule 1), idiotype, IGF1R (IGF-1, insulin-like growth
1 acceptor of the factor), IGHE, IFN-γ, influenza hemagglutinin, Ig E, IgE Fc areas, IGHE, IL-1, IL-2 acceptors (interleukin-22 by
Body), IL-4, IL-5, IL-6, IL-6R (interleukin-6 receptor), IL-9, IL- (insulin-like growth factor 2), integrin egg
(α 4, α IIb β 3, α v β 3,4 β 7 of α) in vain, IL-12, IL-13, IL-17, IL-, interferon gamma inducible protein ITGA2, ITGB2,
KIR2D, LCK, Le, Legumain, Lewis-Y antigen, LFA-1 (Lymphatic diseases, CD11a), α 5 β 1,6 β of α
4, α 7 β 7, α 11 β 3, α 5 β 5, α v β 5, LHRH, LINGO-1, lipoteichoicacid, LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-
2, MAGE-1, MAGE-2, MAGE-3, MAGE A1, MAGE A3, MAGE 4, MART1, MCP-1, MIF (macrophage movement suppression
The factor processed or gly-cosylation-inhibiting factor (GIF)), MS4A1 (4 domain subfamily A members of cross-film
1), MSLN (mesothelin), MUC1 (mucin 1, (MUC1) or polymor-PHIC mucins that cell surface is associated
(PEM)), MUC1-KLH, MUC16 (CA125), MCP1 (MCP 1), MelanA/MART1, ML-IAP, MPG,
MS4A1 (4 domain subfamily A of cross-film), MYC N, myelin associated glucoprotein, Myostatin, NA17, NARP-1, NCA-90
(G-Ag), Nectin-4 (ASG-22ME), NGF, neural apoptosis regulatory protein enzyme 1, NOGO-A, Notch receptor,
Nucleolin, Neu oncoprotein NY-BR-1, NY-ESO-1, OX-40, OxLDL (OxLDL ELISA), OY-
TES1,P21,p53nonmutant,P97,Page4,PAP,Paratope of anti-(N-glycolylneuraminic
Acid), PAX3, PAX5, PCSK9, PDCD1 (PD-1, apoptosis albumen 1, CD279), PDGF, PDX1, PAX5,
Paratope (paratope of anti-N-glycolylneuraminic ac- (the platelet-derived lifes of α types of PCSK9, PDCD1
Growth factor receptor body), PDGFR- β, PDL-1, PLAC1, PLAP sample testis alkaline phosphatases, platelet derived growth factor receptor β,
Sodium phosphate cotransports albumen, PMEL17, poly sialic acid (PR1), prostate cancer, PS (phosphatidylserine), prostate gland cancer cell,
Pseudomonas aeruginosa, PSMA, PSA, PSCA, rabies virus glucoprotein, RHD (Rh polypeptides 1 (RhPI), CD240), rhesus macaque because
Son, RANKL, RhoC, Ras mutant, RGS5, ROBO4, Respiratory Syncytial Virus(RSV), RON, sarcoma translocation breakpoint, SART3, hardening
Albumen, SLAMF7 (SLAM family members 7), Selectin P, SDC1 (Syndecan 1), sLe (a), Somatomedin C,
SIP growth hormone release inhibiting hormones, Human sperm protein 17, SSX2, STEAP1 (six cross-film epithelium antigens of prostate 1), STEAP2, STn, TAG-72
(the relevant glycine φt cell receptor of tumour, T cell transmembrane protein, TEM1 (tumor endothelial marker 1), TENB2, Tenascin
C (TN-C), TGF- α, TGF-β (transforming growth factor β) TGF-β 1, transforming grouth factor beta 2, Tie (CD202b), Tie2, TIM-
1 (CDX-014), Tn, TNF, TNF-α, TNFRSF8, TNFRSF10B (A member of the TNF receptor family 10B),
TNFRSF13B (A member of the TNF receptor family 13B), TPBG (trophoderm glycoprotein), TRAIL-R1 (neoplasm necrosises
Apoenzyme inducing ligand receptor 1), TRAILR2 (death receptor 5 (DR5) (catenin) signal transduction 2, MUC1, tweak receptor,
TYRP1 (glycoprotein 75), TRP-2, tyrosinase, VCAM-1 (CD106), VEGF, VEGF-A, VEGF-2 (CD309), VEGFR-
VEGFR2 or vimentin, the cell or any epidermal growth factor of WT1, XAGE1 or any insulin growth factor receptor of expression
Sub- acceptor.
20. tumour cell according to claim 18 is selected from lymphoma cell, myeloma cell, nephrocyte, breast cancer cell is preceding
Row adenocarcinoma cell, ovarian cancer cell, colorectal cancer cell, stomach cancer cell, epidermoid carcinoma cell, small cell lung cancer cell,
Non-small cell lung cancer cell, testicular cancer cell, or that cannot adjust, quick growth rate and division and to cause appointing for cancer
What cell.
21. a kind of pharmaceutical composition include dose therapeutically effective claim 2 and/or 8 coupling compound and pharmaceutically may be used
Salt, carrier, diluent or the excipient of receiving, for treating or preventing cancer, or autoimmune disease or infectious disease.
22. according to claim 2, conjugate or compound any one of 4,8 or 12, wherein " Drug " is selected from toxin,
Chemotherapeutant, drug molecule, antibiotic, radio isotope, nucleic acid decomposition enzyme and/or chromophoric group molecule.
23. conjugate or compound according to any one of claim 1,5 or 6, wherein described;Chain junctor can contain by
Following components:6- maleimidocaproyls (MC), maleimide propiono (MP), valine-citrulline (val-cit),
Alanine-phenylalanine (ala-phe), lysine-phenylalanine (lys-phe), to aminobenzyloxycarbonyl (PAB), 4- is thio
Valerate (SPP), 4- (N- maleimidomehyls)-hexamethylene -1- carboxylate MCC), 4- Thiobutyric acids ester (SPDB), Malaysia
Acid imide ethyl (ME), the thio -2- hydroxysufonyls butyrates of 4- (2- sulfo groups-SPDB), two mercaptan of pyridine radicals (PySS), alcoxyl
Base amino (AOA), acetenyl oxygen (EO), 4- methyl -4- dithiopentanoic acids (MPDP), azido (N3), alkynyl, disulfide group, peptide
And/or (4- acetyl group) Aminobenzoate (SIAB).
24. according to the conjugate or compound of any one of claim 2,8 or 22, wherein " Drug " is selected from tubulysins,
Maytansinoid, taxoid (taxane), CC-1065 analogs, daunorubicin and doxorubicin compound, benzodiazepine *
Tall and erect dimer (is selected from as pyrrolo- Benzodiazepine dimer, tomamycin dimer, indoline and Benzodiazepine dimer, miaow
Azoles and Benzodiazepine or oxazolidine and Benzodiazepine dimer), add Citropten and enediyne antibiotic, D actinomycin D,
Azaserines, bleomycin, epirubicin, tamoxifen, idarubicin, the auspicious statin of dolastatin/Austria is (selected from single first
Ji Aorui statin E, auspicious statin MMAE difficult to understand, auspicious statin MMAF difficult to understand, auspicious statin PYE, auristatin TP, Ao Rui difficult to understand
Statin 2-AQ, auspicious statin 6-AQ difficult to understand, auspicious statin EB (AEB) difficult to understand and auspicious statin EFP (AEFP) difficult to understand), block meter Xing, thiophene more
For group, vincristine, hemiasterlins, nazumamides, microginins, radiosumins,
Alterobactins, microsclerominmins, theonellamides, esperamicins, analogs and derivatives.
25. according to the compound of claim 1 or 4, it contains the functional group that can be reacted with cell binding agent, includes such as following formula
5,9,16,19,27,29,30,33,35,40,47,50,51,53,62,63,65,68,69,74,75,77,84,85,88,89,
94,95,99,100,108,109,114,115,121,123,124,135,136,141,142,144,147a,147b,147c,
147d, 153,158,172,173,174,182,183,193,194,195,202,203,204,207,208, or shown in 209:
Wherein m1,m2And m3It is halogen independently to be 0~24, X, R1In definition and claim 1,2,13, or 14 with Drug
It is identical.
26. formula 6,17,10,12,20,22,28,31,34,36,37,41,48 is included according to the compound of claim 2 and 3,
52,54,64,66,70,71,76,78,86,87,90,96,97,101,102,110,116,125,126,127,137,143,
145,148a, 148b, 148c, 148d, 159,184,185,194,197,205,210, it is as shown below:
Wherein m1,m2And m3It is halogen independently to be 0~24, X, R1, in q and the definition of Drug and claim 1,2,13, or 14
It is identical.
27. according to claim 2,7, or the conjugate any one of 8, it has external, in vivo or in vitro cell killing
Activity.
28. such as the coupling compound any one of claim 2,7 and/or 8, it can include the day of 1~20 unit
So or alpha-non-natural amino acid peptide, either aminobenzyl unit either 6- maleimidocaproyls unit or two sulphur
Compound unit, or thio-ether units, or hydrazone unit, or triazole unit, or alkane oxime unit.
29. the coupling compound according to any one of claim 2,7 or 8, wherein the connection component of the present invention can be by
Protease cracking.
30. comprising dose therapeutically effective claim 2,7 or/and 8 coupling compound pharmaceutical composition, for selected from
Chemotherapy agents, radiotherapy, immunotherapeutic agent, autoimmune disorder reagent, anti-infective agents or the collaboration of other conjugates are effective
Treat or prevent cancer or autoimmune disease or infectious disease.
31. one or more of the synergist according to claim 30 in agents:Orencia, acetic acid Ah's bit
Dragon, paracetamol/hydrocodone, adalimumab, Afatinib 2-maleate, alemtuzumab, alitretinoin, Love Capital
Trastuzumab maytansine, A meter Zhu monoclonal antibodies, amphetamine salt-mixture (amphetamine/dextroamphetamine), Anastrozole, A Li
Piperazine azoles, atazanavir, Aunar pearl monoclonal antibody, Atorvastatin, pazopanib, Baily department he, Avastin, kappa it match, card
Rich to replace Buddhist nun, Bexarotene, Beaune spits monoclonal antibody, bortezomib, bosutinib, this appropriate former times monoclonal antibody, budesonide, budesonide/good fortune
Mo Teluo, buprenorphine, capecitabine, Carfilzomib, celecoxib, match is vertical to replace Buddhist nun, Cetuximab, cyclosporine, Xi Naka
Plug, gram azoles replace Buddhist nun, and dabigatran, dabrafenib, up to than mooring Ting Aer enamels, Prezista, imatinib mesylate, is replaced up to sand
Buddhist nun, the diphtheria toxin of denileukin -2, ground promise monoclonal antibody, divalproex sodium, dexamethasone, R-lansoprazole, dexmethylphenidate, ground is exerted
Appropriate former times monoclonal antibody, Doxycycline, Duloxetine, emtricitabine/rilpivirine/tenofovir disoproxil fumarate, emtricitabine/
Tenofovir/efavirenz, Enoxaparin, En Zuolu amine, Epoetin α, Tarceva, esomeprazole, eszopiclone,
Etanercept, everolimus, Exemestane, according to ezetimibe, according to ezetimibe/Simvastatin, fenofibrate, Filgrastim,
Fingomode, fluticasone propionate, fluticasone/salmeterol, fulvestrant, Gefitinib, copaxone, acetic acid Ge Sherui
Woods, Yi Qu replace Buddhist nun, her cloth is taken smooth for not monoclonal antibody distant, and Buddhist nun, Ai Dailalisi, infliximab, insulin aspart, ground are replaced according to Shandong
Special insulin, insulin glargine, insulin lispro, interferon beta 1a, interferon beta 1b, Lapatinib, easy Puli's nurse agate, isopropyl support
Bromine ammonium/salbutamol, acetic acid orchid receive peptide, lenalidomide, methanesulfonic acid Lay that replace woods, Letrozole, levothyrocine, benefit card
Cause, Linezolid, Liraglutide, two methanesulfonic acids rely Dexamfetamine, MEDI4736, Memantine hydrochloride, ritalin, metoprolol, not
Da Feini, Mometasone, nilotinib receive military monoclonal antibody, difficult to understand, the outstanding trastuzumab in shore difficult to understand, olaparib, Olmesartan,
Olmesartan/Hydrochioro, omalizumab, the fatty-acid ethyl ester of omega -3, Oseltamivir, Oxycodone, Pa Boxini, Pa Li
Pearl monoclonal antibody, Victibix, pabishta, pazopanib, pyridine aldoxime methyliodide (PAM) monoclonal antibody, pemetrexed, handkerchief trastuzumab, streptococcus pneumonia epidemic disease
Seedling, pomalidomide, Pregabalin, Quetiapine, Rabeprazole, 223Ra chloride, Raloxifene, draws for Wei is drawn, Lei Molu is mono-
Anti-, Lucentis, Rui Gefeini, Rituximab, razaxaban, romidepsin, rosuvastatin, phosphoric acid Luso is sharp to replace Buddhist nun,
Salbutamol, sevelamer, silaenafil, takes charge of appropriate former times monoclonal antibody, sitagliptin, sitagliptin/melbine, Solifenacin, rope
La Feini, Sutent, Tadalafei, tamoxifen, telavi, tesirolimus, tenofovir/emtricitabine, testosterone
Gel, Thalidomide (Yi Miaopulin), Tiotropium Bromide, Toremifene, Sibutramine Hydrochloride replace Buddhist nun, Herceptin, vitamin A acid, excellent spy
Gram monoclonal antibody, Valsartan, Vande Thani, Wei Luofeini, Fu Ruisite, VEGF Trap, herpes zoster vaccine, and the like, spread out
Biology, pharmaceutically acceptable salt, carrier or excipient, or combinations of the above.
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CN (2) | CN112125929A (en) |
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CN112386707B (en) * | 2019-08-19 | 2023-08-11 | 辽宁医学诊疗科技研发中心有限公司 | Tumor targeting polypeptide drug conjugate and preparation method thereof |
CN110938035A (en) * | 2019-10-28 | 2020-03-31 | 广西师范大学 | 9-benzenesulfonic acid-10-mianthracene hydrazone and synthesis method and application thereof |
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WO2015151078A2 (en) | 2015-10-08 |
CN108026123B (en) | 2021-02-05 |
EP3307749A2 (en) | 2018-04-18 |
NZ737471A (en) | 2022-02-25 |
AU2023200925A1 (en) | 2023-03-23 |
WO2015151078A3 (en) | 2016-03-10 |
EP3307749A4 (en) | 2019-06-19 |
AU2021201765A1 (en) | 2021-04-15 |
AU2015242210A1 (en) | 2017-12-07 |
WO2015151078A4 (en) | 2016-07-14 |
CN112125929A (en) | 2020-12-25 |
CA2989269A1 (en) | 2015-10-08 |
AU2021201765B2 (en) | 2022-12-08 |
CA2989269C (en) | 2020-09-22 |
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