CN101466391A - Inhibition of tumor growth - Google Patents

Inhibition of tumor growth Download PDF

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CN101466391A
CN101466391A CNA2007800154351A CN200780015435A CN101466391A CN 101466391 A CN101466391 A CN 101466391A CN A2007800154351 A CNA2007800154351 A CN A2007800154351A CN 200780015435 A CN200780015435 A CN 200780015435A CN 101466391 A CN101466391 A CN 101466391A
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厄于斯泰因·雷克达尔
约翰·西居尔·斯文森
巴尔杜尔·斯文比约恩松
格尔德·贝格
利夫·托内·埃利亚森
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Lytix Biopharma AS
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Abstract

The present invention provides the use of a lytic compound, in particular a lytic peptide, in the manufacture of a medicament for inducing adaptive immunity against tumour growth or establishment in a subject, as well as methods of cancer treatment and vaccination.

Description

Inhibition to tumor growth
The present invention relates to the Therapeutic Method of tumor sex organization.Especially, it relates to that the dissolved compound (lytic compound) that causes of peptide makes oncolysis to induce the method for inflammatory reaction by for example using.By causing inflammatory reaction, activated intrinsic and approach acquired immune system, promote tumour-specific immune response.Thisly given the experimenter acquired immunity of anti-corresponding tumor cell, thereby suppressed the growth of secondary tumors immune initiation.
The not controlled growth of cell and division can produce tumor.With diffusion and invasion and attack is standard, and tumor is divided into optimum or pernicious usually.Tissue around malignant tumor can invade and destroy.Its cell also can diffuse to outside former position of tumor.Therefore benign tumor does not have these character, but benign tumor can develop into the pernicious stage, treats benign tumor and malignant tumor all may be useful.For example, oral squamous carcinoma neoplasia is not treated usually, but this situation will soon develop into the pernicious stage, just has to this moment by operation tongue partly or entirely be excised.In addition, benign tumor itself may also be bad, if particularly they are very big and to be grown in vitals contiguous, therefore, also may wish benign tumor treated and reduce subsequently similarly benign tumor thus.
Break away from and be diffused into by blood flow or lymphsystem that the process of other organ is known as transfer in the body from primary tumor from the cell of malignant tumor.When these cells reach new when regional in the body, they can be invaded tissue and continue division, and can form new tumor.This new tumor is commonly referred to as " secondary tumors ".
The growth of secondary tumors often constitutes a threat to experimenter's health, therefore needs exploitation to suppress the method for secondary tumors formation or growth.
On long terms, owing to existing and undetected micrometastasis growth subsequently before of tumor cell, late period, the excision of entity tumor was normally invalid.In the patient with breast cancer, this is recurrence and final murderous main cause always.Postoperative, the frequent dormancy of the cell of distribution is in the cell cycle G0 phase.Therefore, these nonproliferating cells often have resistance to chemotherapy.Late period, head and neck cancer patient's cure rate did not significantly improve in 10 years in the past.Among these patients, the cases of great majority recurrences are part or locality, and so that they be difficult to be existed by approaching mode.An example is a local advanced esophageal carcinoma, and they should not be performed the operation and poor prognosis usually.
The obstacle of seeking the method maximum that suppresses the secondary tumors growth is: tumor is that origin comes from the plastidogenetic of experimenter self.Immune system is an abnormal cell with these cell recognitions as possible.External source or paracytic identification generally include and detect molecule and the antigen that is positioned on the cell surface.The most tumors cell has and at least aly is different from Normocellular antigen, and in most of the cases described antigen is that specific cancer types is specific.Some tumor cells may have multiple antigen, and other cell may only have the antigen of single type.Antigenic type, different antigenic number and antigenic dominance all may influence immune system these tumor cells are identified as unusual probability on the cell surface.The antigen that the tumor of most types has is considerably less, and perhaps only having difficult is ectogenic antigen by immune system recognition, so they can escape from immune identification and destruction.Therefore, the antigenic kind that had of any specific tumors type and quantity play an important role in how in " immunogenicity " of determining tumor." immunogenicity " means the ability that causes immunne response, and therefore a kind of immunogenicity of tumor is strong more, and then it may and be attacked by immune system recognition more.
Carry out many trials and helped immune system opposing tumor.A kind of early stage method comprises by immune system being carried out generality to stimulate, and for example, causes general immunne response by using antibacterial (live or deactivation), and it also can be used to resist tumor.This is also referred to as nonspecific immunity.
Nearest some comprise at the method that helps immune system specific identification tumor specific antigen uses tumor specific antigen to the experimenter, particularly co-administered with adjuvant (the known material that causes or improve immunne response).This method needs in-vitro separation and/or synthetic antigen, and this is not only expensive but also consuming time.A kind of alternative method of dissimilar cancer return rates that can reduce is for adopting immunization therapy.All there are some difficulties in most of cancers when using immunization therapy.Usually do not identify all tumor specific antigens, for example, in the breast carcinoma, the known antigens of being found accounts for the 20%-30% of total tumor.Therefore, use the tumour-specific vaccine only to obtain limited success.
Still be starved of the alternative method that suppresses the secondary tumors growth or form.
The wonderful discovery of the inventor causes the cell that dissolved compound can be used for dissolving first tumor in patient's body, and therefore suppresses the growth of secondary tumor in described patient's body.Described in this paper embodiment, use causes the dissolving peptide and has proved this effect.Some other causes dissolved compound is known in the art, and the example comprises detergent such as Triton X-100 and sour example hydrochloric acid.
Based on the ability of its dissolving tumor cell, proposed to cause the purposes that the dissolving peptide is used for oncotherapy (Risso et al., Cell.Immunol.[1998] 107 and WO 01/19852) in the art.Relevantly thisly cause that the dissolving peptide not only is used for the treatment of first tumor, the discovery that also suppresses second tumor growth is unexpected fully.
Without being limited by theory, the dissolving of suspecting first tumor has caused inflammatory reaction.Described dissolving can cause the exposure of cancerous cell specific antigen." exposure " means and makes that antigen can be allogenic material by immune system recognition.
Therefore " exposure " comprise make antigen easier by immune system near and/or make it pass immune system with a kind of more may being by the mode of immune system recognition, for example, it is on cell fragment, rather than on whole cell.Therefore, term " exposure " comprises released antigen in the intercellular substance, but also comprises other variation on any cellularity, makes antigen become easier of immune system recognition.
But specific b cells and/or T cell and make these cell some of them maturations become memory cell in the antigen activating immune system that exposes.Memory cell has the very long life-span usually, and when their for the second time or when running into same antigen again, they are than virgin type (virgin) B or the T cell is easier replys.This generation and the process of keeping special memory cell are commonly referred to as " immunological memory " or " acquired immunity ".Therefore, the beat all discovery of the present inventor causes the immunological memory that solubilising reagent (for example peptide) can be used to inducing antitumor.
The present inventor has confirmed just not observed second growth of tumor by with after causing dissolved compound and successfully treating tumor.In pattern experiment, cause dissolved compound from previous usefulness and successfully treat the adoptive transfer of the spleen of the animal of (healing) (immunity) cell and demonstrate and give untreated receiver with specific immunity.Therefore, accept can to eliminate the tumor of implantation from the receiver of the splenocyte of curing mice before, and accept from be untreated (
Figure A200780015435D0007134655QIETU
) receiver of splenocyte of mice can not eliminate the tumor of implantation.These results prove that protective effect is because previous successful oncolysis has been given the secular specific immunity of tumor, particularly tumor of the same type subsequently subsequently.
And tumor is induced general immunosuppressant usually, so viewed immune initiation is very favorable among the present invention.
Therefore, the invention provides the method for in the experimenter, inducing acquired immunity on the one hand, described method comprises the dissolved compound that causes of described experimenter being used effective dose, and the wherein said dissolved compound that causes is by dissolving generation inhibition second tumor growth of the first tumor inner cell or the immunne response of formation.
Briefly, the invention provides the method for inducing acquired immunity in the experimenter, it comprises the dissolved compound that causes of described experimenter being used effective dose.
In this article, acquired immunity should be understood that the immunity of neoplasm growth or formation, the particularly anti-and described same or analogous tumor of the dissolved tumor of the direct targeting of dissolved compound that causes.Therefore, cause dissolved compound and be designed or be chosen to be used for dissolving tumor cell.
From another angle, the invention provides method for cancer among the treatment experimenter, it comprises the dissolved compound that causes of described experimenter being used effective dose, and wherein saidly causes the dissolving of dissolved compound by the first tumor inner cell and produces the immunne response that suppresses second tumor growth or formation.
Again on the other hand, inventors of the present invention find to cause dissolved compound and can be used for first tumor treatment to produce the vaccine of anti-second tumor.Vaccine is that original position produces, i.e. induce immune response and produce the antigen of immunological memory because the dissolving of tumor cell and be and pass immune system.It is different fully with vaccine of the prior art that original position (in the body) produces antigenic this class vaccine the experimenter being used for example the causing dissolved compound of peptide, and the latter normally prepares antigen and then is applied to the experimenter at laboratory (promptly external).
Therefore, another aspect the invention provides and causes the purposes of dissolved compound in preparing the medicament that is used as neoplasm growth or development vaccine." advolution " comprises the formation of tumor.The present invention also provides by described patient is used and has caused dissolved compound (preferably cause dissolving peptide) and come the experimenter is carried out the method for immunity inoculation with neoplasm growth or development.Mentioned " vaccine " and " immunity inoculation " are all represented preventive effect, and therefore, although have having the favourable direct Therapeutic Method of tumor, an important motivation is prevention or alleviates following tumor formation, grows or develop.
As if without being limited by theory, believe that the dissolving incident induces inflammatory reaction, it is for the elimination of first tumor and induce the acquired immunity protection of anti-one or more second tumors extremely important.The inventor's discovery proof (has complete immune system) in the syngeneic animal model often can successfully make the tumor of winning disappear fully, and in nude mice (not having the functional immunity system), first growth of tumor is suppressed and can't surpass 50%.Therefore, the some parts that dissolves first tumor may be just enough, and it can promote the directed immunne response to the tumor remaining cell, and the protectiveness antitumor memory of inducing anti-secondary tumors.
Therefore, in subject, produce the antineoplastic acquired immunity, the particularly anti-and dissolved same or analogous tumor of first tumor type.
The present invention also provides the purposes that causes in dissolved compound produces acquired immunity in subject is induced in preparation the medicament.Especially, the invention provides the purposes that causes in dissolved compound produces acquired immunity in subject is induced in preparation the medicament, wherein saidly cause the dissolving of dissolved compound by cell in first tumor and produce the immunne response that suppresses second tumor growth or formation.
The present invention also provides and has been used to induce the dissolved compound that causes that produces acquired immunity in the subject.More particularly, the invention provides and be used to induce the experimenter to produce the dissolved compound that causes of acquired immunity, wherein saidly cause the dissolving of dissolved compound by cell in first tumor and produce the immunne response that suppresses second tumor growth or formation.
Therefore, " first tumor " is meant also planning by making it directly and immediately dissolve the tumor for the treatment of of having identified in the experimenter.First tumor is primary tumor normally, i.e. first tumor of this type that generation and/or quilt are identified out in subject.Yet described " first tumor " in fact also may be secondary tumors.This situation may appear at primary tumor and remove from the experimenter in the example of (operation or other method).Therefore, " first tumor " and do not mean that it to be in esoteric first tumor of experimenter; The use of term " first " is relevant with the order of each incident generation in the method for the present invention.
Usually can be locally applied to first tumor with causing dissolved compound, for example, be injected into this first tumor or its immediate vicinity, although the general administration is also interim in advance.Injection can for example be produced in a usual manner, as adds antiseptic of p-Hydroxybenzoate and so on for example or the stabilizing agent of EDTA for example.Subsequently described solution is packed in injection vials or the ampoule.
A target of the inventive method and purposes is to produce immunological memory and suppress second growth of tumor or formation among the dissolved patient of first tumor in receptor thus.Growth inhibited comprises disappearing of tumor, and promptly size reduces, and preferably is reduced to tumor complete obiteration and/or no longer can detected degree.Suppress also to comprise the formation that prevents second tumor.Therefore, effective treatment according to the present invention can mean the patient and develops no longer after first tumor being carried out initial dissolution treatment that can detected tumor.Growth inhibited also comprises the normal speed that reduces tumor growth, slows down or prevent the foundation of blood vessel network in the entity tumor.
Term " second tumor " typically refers to secondary tumors, is also referred to as transfer, just by from other tumor and be diffused into the tumor that the cell at new position develops into.Yet within the scope of the invention, term " second tumor " also can comprise primary tumor.When this situation appears at two or more tumor coexistences, for example two independent primary tumors that occur, an or constitutional and a secondary tumors and wherein directly treat described secondary tumors to induce the immunological memory of anti-such tumor (comprising primary tumor) with causing the dissolving peptide.
Term " second " tumor comprises literal second and subsequently any or other tumor.Therefore, can suppress the growth of several secondary tumorses according to the present invention.Described " second " tumor also may be the tumor that recurs after initial therapy, and wherein said initial therapy may adopt conventional therapy (promptly not necessarily by dissolving).
Described first tumor preferably has similar immunogenicity with second tumor, and preferred described first tumor and second tumor are the cancers of same type.It should be understood that in any given tumor, be not that all cells all have identical phenotype, so each cell of tumor may have different antigen.This may cause exposing a large amount of antigens after the dissolving, and the immunological memory of anti-multiple cancerous cell type may be provided.
Because to the inducing of immunological memory, as discussed above, use may not have " second tumor " among the experimenter when causing dissolved compound or detect at least less than.Because initial dissolving incident " initiation " experimenter and activated immune system, therefore think that it is appropriate having produced the original position cancer vaccine.
In the entire article, unless clearly demonstrate in addition in the literary composition, the term " tumor " that any front does not have " first " or " second " to modify all should be understood that to be applicable to first and second tumors.
" dissolving " of first tumor should be understood that to mean the dissolving of the one or more cells of described tumor.Therefore do not need whole tumor dissolving." dissolving " used herein comprises the part of cell and dissolving fully.Be partly dissolved and mean and make the epicyte stabilization removal fully and cause cell component from the cell internal leakage and/or cause the part of adventitia to separate from cell.Antigen presentation does not also require that tumor cell is broken fully.
Preferably, tumor is selected from: lymphoma, carcinoma (carcinoma) and sarcoma, most preferably B cell lymphoma.In melanoma also is encompassed in.Generally speaking, tumor is natural generation, pathologic tumor; As mentioned above, benign tumor can be a target.
Another advantageous applications of the present invention is carcinoid treatment, for example, and the mouth epithelial cells benign tumor.In the past, this class tumor may not treated after making a definite diagnosis at first, but " observing and wait " a period of time.By early treatment, may stop its process to the malignant tumor conversion to this tumor.There is the benign tumor of resistance to be particularly suitable as target to chemotherapy.
The present invention does not relate to the tumor of chemical induction." chemical induction tumor " be meant by human intervention, normally is used for research purpose and the tumor that deliberately causes producing.These belong to " non-natural tumor ".An example of the tumor of chemical induction is by the inductive Meth A of methyl cholanthrene fibrosarcoma.Therefore all related herein tumors should be got rid of this class chemical induction tumor.
Be not anyly to have a mind to cause under the tumorigenic situation tumor that in subject, produces owing to be exposed to environmental chemicals not within the range of definition of " chemical induction tumor ", so these tumors have been contained in the present invention." environmental chemicals " is meant any chemicals that the experimenter can touch naturally, the chemicals that for example airborne, water-borne and/or food is propagated, and these chemicals all exist with low dosage usually.
The experimenter may be anyone or non-human animal, preferred mammal, and optimum is chosen.
" cause dissolved compound " and be meant and anyly can cause the dissolved chemical compound of zooblast.Preferably, cause dissolved compound tumor cell is had quite high specificity, just compare, its meeting optimum solvation tumor cell, thereby the side effect minimum that experimenter's administered compound is stood with suitable healthy cell.
Cause preferably peptide of dissolved compound.It is suitable that to cause the dissolving peptide be known in the art, it for example comprises in WO 00/12541, WO 00/12542, WO 01/19852 and WO 01/66147 and described in following document: Papo N, Shahar M, Eisenbach L, Shai Y. ＂ A novellytic peptide composed of DL-amino acids selectively kills cancer cells in cultureand in mice ＂ .J Biol Chem 2003; 278 (23): 21028-23.
Papo?N，Braunstein?A，Eshhar?Z，Shai?Y.Suppression?of?human?prostatetumor?growth?in?mice?by?a?cytolytic?D-，L-amino?Acid?Peptide：membrane?lysis，increased?necrosis，and?inhibition?of?prostate-specific?antigen?secretion.CancerRes?2004；64(16)：5779-86。
Leuschner?C，Hansel?W.Membrane?disrupting?lytic?peptides?forcancer?treatments.Curr?Pharm?Des?2004；10(19)：2299-310。
Johnstone SA, Gelmon K, Mayer LD, Hancock RE, Bally MB.In vitrocharacterization of the anticancer activity of membrane-active cationicpeptides.I.Peptide-mediated cytotoxicity and peptide-enhanced cytotoxicactivity of doxorubicin against wild-type and p-glycoproteinover-expressing tumor cell lines.Anticancer Drug Des.2000; 15:151-60 and
Selsted?ME，Novotny?MJ，Morris?WL，Tang?YQ，Smith?W，Cullor?JS.Indolicidin，a?novel?bactericidal?tridecapeptide?amide?from?neutrophils.J?BiolChem?1992；267(7)：4292-5。
Causing the dissolving peptide is particularly preferred as causing lytic agent.Usually their half-life shorter, that is to say that they can decompose usually very soon dissolved cell after, for example because due to the protease and similar material that discharge in the cell.Half-life, short meeting reduced systemic-toxic risk, and therefore may have advantage, but the longer in some cases half-life may cater to the need.The half-life of peptide may be controlled, and just increases or shortens as required.For example, the half-life of peptide can prolong by introducing D-aminoacid and/or modification C-end and/or N-end.
Another kind of preferably cause dissolved compound be known or the prediction cause the dissolving peptide the plan peptide.
In this field, replace based on peptide or activity of proteins agent such as therapeutic peptide at present with having active plan peptide suitable on function.Usually, this compounds can be simply with substituting linear flexible main chain for example (C (R) NHCO)- nOr (C (R) CH 2CH 2)- nPerhaps non-linear main chain one class material of cyclohexane extraction condensed ring structure (for example based on) replace (C (R) CONH) of peptide- nMain chain.Except the variation of main chain, side chain functionalities (side chain in the former peptide) exists in a similar manner, makes this chemical compound have similar dissolving vigor.
Known have various molecular libraries and a combinatorial chemistry technique, and they can be used for identifying, selecting and/or synthetic this compounds (Kieber-Emons, T.et al.Current Opinion inBiotechnology 19978:435-441) by standard technique.
The common length of described peptide is at least 3 aminoacid, 4-30 for example, and preferably long 5-30 aminoacid, preferably long 7-25 aminoacid, and can have one or morely, preferably 2-8 is individual, more preferably 4-8 positive charge.Preferably, described peptide comprises big, and for example 4 or more a plurality of, the lipophilic group of preferred 7 or more non-hydrogen atoms, these groups are considered to interact with cell membrane and help dissolving, preferably described peptide to contain 2-6 such group.In a preferred embodiment, cause the dissolving peptide and comprise at least one biphenyl alanine (Bip) and/or at least one diphenylprop propylhomoserin (Dip) residue.Preferred peptide comprises 1-5, for example 2-4 trp residue.
Preferably, causing the dissolving peptide is not the derived peptide of lactoferrin, and more particularly, it preferably is not ring-type lactoferrin (LFB, its primary structure are FKCRRWQWRMKKLGAPSITCVRRAF).
Ester, amide or the cyclic derivatives of peptide or plan peptide class (those peptides of being mentioned particularly) also are that the present invention is desired.Causing the dissolving peptide or intend peptide (or its ester, amide or cyclic derivatives) can its free form or for example use with the form of conjugate or salt.Described salt is officinal salt preferably, for example acetate.In a preferred embodiment, described causing dissolved peptide or intended the form existence of peptide with trifluoroacetic acid (TFA) salt.Trifluoroacetate often uses in chromatographic technique, is used for after peptide is synthetic purification to peptide.
Non-peptide class causes the preferred intra-tumor delivery of solubilising reagent.Causing the dissolving peptide can discharge in this way, but because of itself and the healthy cell with homologue's type compare the selectivity of tumor cell, their also may systemic delivery.Have in this respect higher optionally cause the dissolving peptide be preferred.In addition, all solubilising reagents that cause may for example adopt liposome delivery, dextrin-conjugation, or other suitable carriers solution by the site of alternate manner targeting first tumor.Therefore, non-peptide causes solubilising reagent and also may adopt systemic delivery.
Preferably, the described dissolved compound that causes itself is weak immunogenic, does not more preferably have immunogenicity fully, and promptly itself does not cause any antibody response.
Present invention is described with reference to the embodiment of following indefiniteness below, wherein:
Fig. 1 represents the development with A20B cell lymphoma in the Balb/c mice of different peptide treatments back.
Fig. 2 represents successfully to treat with different peptides the development of tumor in the mice of A20 entity tumor renewed vaccination A20 cell after month.
Fig. 3 is illustrated in successfully the effect of renewed vaccination A-20 cell in the animal for the treatment of with Mod 28 or Mod 39.
Fig. 4 is illustrated in successfully the effect of renewed vaccination A-20 cell in the animal for the treatment of with C12.Letter a) with b) the different mice of expression.
Fig. 5 is illustrated in successfully the effect of renewed vaccination A-20 cell in the animal for the treatment of with Mod 28 or Mod 39.Positive control shows the growing state of A20 cell in the mice of not using the peptide pretreat.
Fig. 6 represents the initial action of NDDO1 to the C26 colon cancer.
Fig. 7 is illustrated in successfully the effect of renewed vaccination C26 cell in the mice for the treatment of with NDDO1.
Fig. 8 represent than first experiment (
Figure A200780015435D0013135207QIETU
) untreated mice, the adoptive transfer of the anti-A20 cancer immunity of specificity of the mice (causing the treatment of dissolving peptide) of curing from success with Mod39.Acceptance can be repelled the tumor of implantation from the receiver of the spleen cell of the mice for the treatment of before, and accept from be untreated (
Figure A200780015435D0013135221QIETU
) receiver of spleen cell of mice can not repel the tumor of implantation.
Embodiment
Embodiment 1
A) homology Balb/c mice is used as model system.By the cell (5 * 10 of subcutaneous injection with A20 B cell lymphoblastoma 6Individual) the inoculation mice.Make tumor growth to 20-30mm 2Size.Mice is divided into only one group of 6-8 at random, and directly treats tumor with the peptide that is selected from following table 1.Described treatment comprises that the peptide solution of injecting 50 μ l once a day so that the peptide of 0.5mg to be provided, injected three days continuously.
By measuring the development that the tumor size is come tracking of knub.As can be seen from Figure 1, control tumor (treatment) showed size and continues to increase in 15 days.Can cause tumor size to reduce with the treatment of the peptide in the table 1 tumor, thereby make the apparent upward complete obiteration of tumor.
Table 1: peptide
Title Sequence
Lfcin?B H 2N-FKCRRWQWRMKKLGAPSITCVRRAF-COOH
Model?28 H 2N-KAAKKAAKAbipKKAAKbipKKAA-COOH
Model?39 H 2N-WKKWdipKKWK-COOH (D type and L type)
C12 H 2N-KAAKKAbipKAAKAbipKKAA-COOH
The bip=biphenyl alanine
Dip=diphenylprop propylhomoserin
B) use A20 B cell lymphoblast tumor (5 * 10 again 6Individual) inoculation successfully eliminate A20 B cell lymphoblast tumor as mentioned above mice.Untreated mice is as negative control.No longer further administration for peptides or any other antitumor agent.The result as shown in Figure 2.
When untreated mouse inoculation tumor cell, tangible tumor growth has taken place.When the mice reuse tumor cell inoculation of before treat with cLfinB, some initial tumor growths have taken place, but just be significantly less than the tumor in the control mice and the generation of further not growing in the 1st day tumor wherein.Even notice some tumor regression.
With the mice that tumor cell inoculation had before been treated with C12 or L-Mod 39, begin very little tumor to occur, but complete obiteration after the 6th day or the 10th day respectively.
Embodiment 2
In homology Balb/c mice, the three kinds of anti-A20 B of different peptides cell lymphoblast antitumor activity against various tumors have been studied.As definition among the embodiment 1, described peptide is Model 28, Model 39 and C12.With tumor cell (5 * 10 6Individual) subcutaneous vaccination is in mouse web portion, and tumor grew to suitable dimensions (20-30mm before with the peptide treatment 2).Mice is divided into only one group of 5-6 at random, and with 0.5mg/50 μ l peptide tumor is carried out tumor inner therapeutic, continuous three days once a day.Measure tumor size (long and wide is average) with electronic caliper.After three weeks, the mice (promptly showing complete tumor regression) that success is treated is accepted the tumor cell of equal number and same type under aforesaid condition of similarity.The result is shown in Fig. 3-5.
Embodiment 3
In the mice C26 model of colon cancer of in homology Balb/c mice, setting up, the anti-tumor activity of peptides such as Ad-LFB 14-31A2,3,6,10,17, F7, R4, K11, L14-NH2, (NDDO1) is tested.With the C26 cell (among the 50 μ l 5 * 10 6Individual cell) subcutaneous vaccination is in mice (3) abdominal part, and tumor grew to suitable dimensions (20-30mm before begin treatment 2).In the time of the 7th day, with 0.5mg/50 μ l peptide tumor is carried out tumor inner therapeutic once a day, continuous three days, and the development of tracking of knub.In a mice, obtained tumor disappear fully (Fig. 6).In this mice, subcutaneous vaccination C26 tumor cell (among the 50 μ l 5 * 10 again after peptide treated for three weeks 6Individual cell).Under the situation without any other treatment, tumor disappears after initial growth (Fig. 7), shows that described mice has obtained acquired immunity and replied.
Embodiment 4
The initial tumor treatment
Select homology Balb/c mice to be used for research by causing dissolving peptide (H as model system 2N-WKKWdipKKWK-COOH-Mod 39) the long-term antineoplastic immune power of the initial therapy anti-A20 B cell lymphoblastoma of giving.At mouse web portion subcutaneous vaccination tumor cell (5 * 10 6Individual), tumor grew to suitable dimension (20-30mm before begin treatment 2).With 0.5mg/50 μ l peptide mice is carried out tumor inner therapeutic once a day, continuous three days, and the development of tracking of knub.In 3 weeks behind oncolysis, select the donor (through treatment donor) of the mice of successfully treatment as the spleen cell adoptive transfer.
Spleen cell shifts
First day-to untreated (
Figure A200780015435D0015135505QIETU
) the receiver mice carry out 500 cGy total irradiation (Total Body Irradiation, TBI), prepare to accept adoptive transfer from the immunocyte of spleen donor.
Second day-as previously mentioned method prepare hang oneself treatment donor mice and untreated mice do not contain erythrocytic splenocyte single cell suspension (Ward, B.A et al., J.Immunology Aughust.1988, vol 141 pl047), except wherein replacing ammonium chloride to remove erythrocyte with sterilized water.According to Bogen B.et al., Eur J Immunology, May 1983, vol 13 (5), the method described in the pages 353-359, with donor spleen cells (about 4,000 ten thousand) intravenous injection to the tail vein of receptor mice.
The 3rd day-with tumor cell (5 * 10 6Individual) subcutaneous vaccination is in mouse web portion, and by following the trail of its growth with the size of kind of calliper tumor.
The result shows that the immunocyte that shifts makes and accepts mice and obtain immunity (Fig. 8-" healing " group) to the same type tumor from the mice that previous success is treated.On the contrary, from the donor mice that is untreated, shift immunocyte after, the tumor of implantation do not reduce (Fig. 8-" be untreated (
Figure A200780015435D0016135557QIETU
) " group).These results show that the protection effect is that described oncolysis has been given the secular specific immunity to this tumor type owing to previous successful oncolysis.
Embodiment 1-3 adopts trifluoroacetic acid (TFA) salt form of mentioned peptide to implement.

Claims (37)

1. cause dissolved compound and be used for purposes in the medicament of experimenter's inducing antitumor growth or the acquired immunity that forms in preparation.
2. cause dissolved compound in preparation as the purposes in the medicament of the vaccine of neoplasm growth or formation in the experimenter.
3. according to the purposes of claim 1 or 2, the wherein said dissolved compound that causes produces the immunne response that suppresses the formation of second tumor, growth or develop by the cell that dissolves first tumor.
4. according to purposes any in the claim 1 to 3, the wherein said dissolved compound that causes is a peptide.
5. according to the purposes of claim 4, the length of wherein said peptide is at least 3 aminoacid, and has one or more positive charges.
6. according to the purposes of claim 4 or 5, wherein said peptide comprises big lipophilic group.
7. according to the purposes of claim 6, wherein said big lipophilic group has 7 or more non-hydrogen atom.
8. according to the purposes of claim 7, the wherein said dissolving peptide that causes comprises at least one biphenyl alanine (Bip) and/or at least one diphenylprop propylhomoserin (Dip) residue and/or 1-5 trp residue.
9. according to purposes any in the claim 1 to 3, the wherein said dissolved compound that causes is for intending peptide.
10. according to purposes any in the claim 1 to 9, the described dissolved compound that causes of intra-tumor delivery wherein.
11. according to purposes any in the claim 1 to 10, wherein said growth inhibited is disappearing of tumor.
12. according to purposes any in the claim 1 to 11, wherein said growth inhibited comprises the formation that prevents second tumor.
13. according to purposes any in the claim 1 to 12, wherein said second tumor is a secondary tumors.
14. according to purposes any in the claim 1 to 13, wherein said first tumor has similar immunogenicity with described second tumor.
15. according to the purposes of claim 14, wherein said first tumor is identical with the cancer types of described second tumor.
16. according to purposes any in the claim 1 to 15, wherein said tumor is selected from: lymphoma, carcinoma and sarcoma.
17. according to purposes any in the claim 1 to 15, wherein said tumor is a benign tumor.
18. according to the purposes in previous any claim, wherein said experimenter behaves.
19. the method for the acquired immunity that inducing antitumor forms, grows or develops in the experimenter, described method comprises the dissolved compound that causes of described experimenter being used effective dose.
20. the experimenter is carried out immunity inoculation to resist the method that tumor forms, grows or develop, and described method comprises the dissolved compound that causes of described experimenter being used effective dose.
21. according to the method for claim 19 or 20, the wherein said dissolved compound that causes produces the immunne response that suppresses second tumor growth or formation by cell in dissolving first tumor.
22. treatment experimenter method for cancer, described method comprises the dissolved compound that causes of described experimenter being used effective dose, and the wherein said dissolved compound that causes produces the immunne response that suppresses second tumor growth or formation by cell in dissolving first tumor.
23. according to method any in the claim 19 to 22, the wherein said dissolved compound that causes is a peptide.
24. according to the method for claim 23, the length of wherein said peptide is at least 3 aminoacid, and has one or more positive charges.
25. according to the method for claim 23 or 24, wherein said peptide comprises big lipophilic group.
26. according to the method for claim 25, wherein said big lipophilic group has 7 or more non-hydrogen atom.
27. according to the method for claim 26, the wherein said dissolving peptide that causes comprises at least one biphenyl alanine (Bip) and/or at least one diphenylprop propylhomoserin (Dip) residue and/or 1-5 trp residue.
28. according to method any in the claim 19 to 22, the wherein said dissolved compound that causes is for intending peptide.
29. according to method any in the claim 19 to 28, the described dissolved compound that causes of intra-tumor delivery wherein.
30. according to method any in the claim 21 to 29, wherein said growth inhibited is disappearing of tumor.
31. according to method any in the claim 21 to 30, wherein said growth inhibited comprises the formation that prevents second tumor.
32. according to method any in the claim 21 to 31, wherein said second tumor is a secondary tumors.
33. according to method any in the claim 21 to 32, wherein said first tumor has similar immunogenicity with described second tumor.
34. according to the method in the claim 33, wherein said first tumor is identical with the cancer types of described second tumor.
35. according to method any in the claim 19 to 34, wherein said tumor is selected from: lymphoma, carcinoma and sarcoma.
36. according to method any in the claim 19 to 34, wherein said tumor is a benign tumor.
37. according to method any in the claim 19 to 36, wherein said experimenter behaves.
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