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WO1996040249A1 - Usages therapeutiques du ta99 - Google Patents

Usages therapeutiques du ta99 Download PDF

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Publication number
WO1996040249A1
WO1996040249A1 PCT/US1996/010038 US9610038W WO9640249A1 WO 1996040249 A1 WO1996040249 A1 WO 1996040249A1 US 9610038 W US9610038 W US 9610038W WO 9640249 A1 WO9640249 A1 WO 9640249A1
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Prior art keywords
mab
tumor
mice
melanoma
cells
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PCT/US1996/010038
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English (en)
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Alan N. Houghton
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Memorial Sloan Kettering Cancer Center
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Memorial Sloan Kettering Cancer Center
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Priority to AU61711/96A priority Critical patent/AU6171196A/en
Publication of WO1996040249A1 publication Critical patent/WO1996040249A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3023—Lung
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3053—Skin, nerves, brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the immune response to melanoma has been studied more extensively than to any other human cancer. Dissection of the immune response to melanoma has shown that differentiation antigens expressed by normal melanocytes and related neuroectoderm-derived cells are dominant antigens recognized by the immune system [3,5-16] .
  • melanoma autoantigens are proteins of the tyrosinase family. Tyrosinase (the product of the albino locus) is the prototype molecule, and other members include gp75 or tyrosinase-related protein-1 (the product of the Jrown locus) and gplOO (the presumed product of the silver locus) [17-19] .
  • the immune system can recognize differentiation antigens that are selectively expressed on malignant cells and their normal cell counterparts. However, it is uncertain whether immunity to differentiation antigens can effectively lead to tumor rejection.
  • the mouse brown locus protein, gp75 or tyrosinase-related protein-1 is a melanocyte differentiation antigen expressed by melanomas and normal melanocytes.
  • the gp75 antigen is recognized by autoantibodies and autoreactive T cells in persons with melanoma.
  • mouse antibodies against gp75 were passively transferred into tumor- bearing mice.
  • Passive immunization with a mouse monoclonal antibody against gp75 induced protection and rejection of both subcutaneous tumors and lung metastases in syngeneic C57BL/6 mice, including established tumors.
  • Passive immunity produced coat color alterations but only in regenerating hairs.
  • This system provides a model for autoimmune vitiligo and shows that immune responses to melanocyte differentiation antigens can influence mouse coat color. Immune recognition of a melanocyte differentiation antigen can reject tumors, providing a basis for targeting tissue autoantigens expressed on cancer.
  • FIG. 1 Protective immunity induced by mAb TA99 against B16F10 melanoma cells.
  • Melanoma cells (5 x 10 4 ) were injected subcutaneously in 0.1 ml normal saline into the flank of C57BL/6 mice. Mice were treated intraperitoneally with (A) control mouse IgG2a mAb UPC10 or (B) mAb TA99, injected at a dose of 150 ⁇ g diluted in
  • TA99 mAb was purified from ascites by protein A affinity column. There were eight mice in each group. Tumors were assessed three time per week by palpation and inspection. Tumor size (ordinate) was measured in millimeters using calipers. The longest surface diameter (a) and its perpendicular width (b) were measured, and tumor size reported as a x b. Time (abscissa) is presented in days from tumor challenge
  • FIG. 2 Protective immunity by different doses of mAb TA99 against B16F10 melanoma.
  • B16F10 cells were injected subcutaneously in the flank of C57BL/6 mice (see legend of Figure 1) .
  • Mice were treated intraperitoneally with control mAb UPC10 150 ⁇ g (1) or mAb TA99 at doses of 150 ⁇ g (n) , 75 ⁇ g (A) or 37.5 ⁇ g (V) per dose as described in the legend of Figure 1.
  • Tumors were assessed four times per week by palpation and inspection. Mice were scored as tumor-free or tumor- bearing and the proportion of tumor- bearing mice (ratio of tumor-bearing/total number of mice per group) was calculated for each time point.
  • FIG. 3 Anti-tumor effects of mAb TA99 on B16F10 lung metastases.
  • Syngeneic C57BL/6 mice were injected intravenously through the tail vein with lxlO 5 B16F10 melanoma cells in 0.1 ml sterile saline. Mice were treated intraperitoneally with control mAb UPC10 or mAb TA99, 150 ⁇ g dose, three times per week (days 0, 2, 4, 7, 9 and 11) .
  • mice were sacrificed and surface lung metastases were scored and counted as black nodules under a dissecting microscope. There were eight mice in each group. This experiment was repeated five times. Error bars represent one standard deviation.
  • FIG. 4 Anti-tumor effects of mAb TA99 on established B16F10 lung metastases.
  • C57BL/6 mice were injected intravenously with B16F10 melanoma (see legend of Figure 3) .
  • Mice (five to nine mice in each group) were treated intraperitoneally with either control mAb UPC10 or mAb TA99 600 ⁇ g/dose three times per week for two weeks starting day 0 (6 hours after tumor challenge), day 2, day 4 or day 7.
  • Surface lung metastases were detected by day 4-6 under a dissecting microscope and by day 7-8 by eye.
  • mice were sacrificed and lung metastases were counted. This experiment was performed three times (daily doses of mAb TA99 between 300 and 1000 ⁇ g) . Error bars represent one standard division.
  • FIG. 5 Evaluation of potential effector functions in rejection of B16F10 ling metastases induced by mAb TA99.
  • C57BL/6 mice were challenged intravenously with melanoma cells (see legend of Figure 3) and treated with control mAb UPC10 or mAb TAOO 150 ⁇ g dose three times per week (days 0, 2, 4, 7, 9 and 11) for two weeks. Mice were sacrificed on day 18. There were 5 to 7 mice per group. This experiment was repeated twice. Depletion of CD4+ and CD8+ T cell subsets in vivo was accomplished by intraperitoneal administration of rat mAb GK1.5 (anti-CD4) and mAb 2.43 (anti-CD8) (from the American Type Culture Collection, ATCC) .
  • Natural killer cell depletion was performed using mAb PK1.36 (anti-NK-1.1) (from ATCC) . Monoclonal antibody preparations (0.2 ml) were injected intraperitoneally at day -3 and every 7 days thereafter. Throughout experiments, these treatments were shown to deplete respective T cell subpopulation > 98% as determined by indirect immunofluorescence staining and cytofluorometric analysis of peripheral blood, thymus, and spleen. Depletion of
  • NK cells from splenocytes was demonstrated in 4 hr 51 Cr-release assays with YAC cells as targets (effector-to-target ratios of 100:1, 50:1 and 25:1) .
  • PK1.36 treatment was shown to abrogate Hara et al . NK activity completely.
  • mice were injected intraperitoneally with 10 U cobra venom factor (Diamedex, Miami, FL) on day -1 and every 4 days. Depletion of complement was verified using sensitized rabbit RBC (17) . Error bars represent one standard deviation.
  • FIG 6 Alteration of coat color in C57BL/6 mice treated with mAb TA99.
  • Mice were (6-8 weeks old) were depilated on day -1 over the posterior flank. The same results were observed if the coat was plucked manually or depilated with hair remover (JMC, Inc., Tokyo) .
  • hair remover JMC, Inc., Tokyo
  • mice started treatment with either mAb TA99 (left mouse) or mAb UPC10 (right mouse) three times per week for two weeks (see 5 schedule in Figure 1) at individual daily doses of 600 ⁇ g.
  • the line demarcating the upper border of the shaved coat (dorsal trunk of the animal) can be seen in the control animal (right mouse) .
  • mice treated with mAb TA99 showed patchy depigmentation in areas of regenerating hairs but not in the non-depilated coat, while no alteration in coat color was observed in mice treated with isotype
  • This invention provides a pharmaceutical composition comprising effective amount of TA99 monoclonal antibody and a pharmaceutically acceptable carrier.
  • This invention also provides a pharmaceutical composition comprising effective amount of a humanized TA99 antibody and a pharmaceutically acceptable carrier.
  • This invention also provides a pharmaceutical composition comprising effective amount of an antibody capable of competitively inhibiting the binding TA99 to gp75 and a pharmaceutically acceptable carrier.
  • This invention further provides a method of treating tumor comprising administering effective amount of the above-described pharmaceutical compositions.
  • the tumor is a melanoma.
  • This invention provides a pharmaceutical composition comprising effective amount of TA99 monoclonal antibody and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers means any of the standard pharmaceutical carriers.
  • suitable carriers are well known in the art and may include, but not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solutions, phosphate buffered saline containing Polysorb 80, water, emulsions s ⁇ ch as oil/water emulsion, and various type of wetting agents.
  • Other carriers may also include sterile solutions, tablets, coated tablets, and capsules.
  • Such carriers typically contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols, or other known excipients.
  • excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols, or other known excipients.
  • Such carriers may also include flavor and color additives or other ingredients .
  • Compositions comprising such carriers are formulated by well known conventional methods.
  • an “effective amount” of the pharmaceutical composition is any amount of the pharmaceutical composition effective to inhibit the proliferation of tumor cells or neoplastic cells which express gp75. Methods of determining an “effective amount” are well known to those skilled in the art and depend upon factors including, but not limited to: the size of the patient and the carrier used.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising effective amount of a humanized TA99 antibody and a pharmaceutically acceptable carrier.
  • Methods to synthesize a humanized antibody from a mouse monoclonal antibody are well known in the art.
  • the complete backbone of the mouse antibody may be changed to human backbone.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising effective amount of an antibody capable of competitively inhibiting the binding TA99 to gp75 and a pharmaceutically acceptable carrier.
  • this antibody is a humanized antibody.
  • This invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of an antibody capable of binding the epitope recognized by TA99 antibody and a pharmaceutically acceptable carrier.
  • This invention further provides a method of treating tumor comprising administering effective amount of the above-described pharmaceutical compositions.
  • the tumor is a melanoma.
  • administering means any of the standard methods of administering a pharmaceutical composition known to those skilled in the art. Examples include, but are not limited to intravenous, intramuscular or intraperitoneal administration.
  • B16F10 is a mouse melanoma cell line of C57BL/6 origin kindly provided by Dr. Judith Fidler (MD Anderson Cancer Center, Houston, TX) [20] .
  • B78H.1 is a variant of B16 melanoma that does not express the gp75 antigen.
  • JBRH is a melanoma from C57BL/6 provided by Dr. P. Livingston
  • tumors derived from C57BL/6 mice include the RMA and EL-4 lymphomas,
  • tumor cell were injected subcutaneously in the mouse flank.
  • mice were treated intraperitoneally with mAb TA99 or control mouse IgG2a mAb UPC10 diluted in 0.3-0.4 ml of normal saline.
  • TA99 mAb was purified from mouse ascites by protein A affinity column.
  • F(ab') 2 fragments of mAb TA99 were produced by digestion with pepsin and purification over protein A Sepharose.
  • Control IgG2a mAb UPC10 was from Sigma Chemical Co. (St. Louis, MO) .
  • Injection with control mAb UPC10 did not induce any difference in growth of B16F10 melanoma compared to untreated control mice.
  • the longest surface length (a) and its perpendicular width (b) were measured, and tumor size reported as a x b.
  • lung metastases at 16-20 days after tumor challenge mice were sacrificed and surface lung metastases were scored and counted as black nodules under a dissecting microscope. Surface lung metastases were detected by day 4-7 under a dissecting microscope and by day 7-10 by eye.
  • tissues and tumors were fixed in formalin solution, blocked in paraffin, sectioned every 4 microns and stained with hematoxylin and eosin.
  • Statistical analysis of tumor growth was performed using the Student's ⁇ test or Bonferroni two sided t test, a conservative analysis to allow for multiple comparisons.
  • Antibody treatments in vivo Depletion of T cells in vivo was accomplished by intraperitoneal administration of rat mAb GK1.5 (anti-CD4; IgG2b) and mAb 2.43 (anti- CD8; IgG2b) , and Thyl.2 + cells by mAb 30-H12 [produced by hybridomas from the American Type Culture Collection (ATCC) , Rockville, MD] . These mAb were used as ascites fluids (titer >1:10,000 by staining of mouse thymocytes by flow cytometry) . Monoclonal antibody preparations (0.2 ml) were injected intraperitoneally at day -3 and every 7 days thereafter.
  • mice were injected intraperitoneally with 10 U cobra venom factor (Diamedexz, Miami, FL) on day -1 and every 4 days. Depletion of complement in sera of treated mice was verified using lysis of sensitized rabbit RBC
  • Intracellular expression of gp75 was determined using mAb TA99 in indirect immunofluorescence assays against B16F10 melanoma cells fixed and permeabilized in methanol :acetone (1:1) at 4° C for 15 min. Intracellular expression was confirmed by immunoelectronmicroscopy using protein A labelled colloidal gold particles as described [22] . Cell surface expression was shown by binding of mAb TA99 to intact, live B16F10 cells by enzyme-linked immunoassay (titer >l/10,000) and by protein A mixed hemadsorption assay (titer >l/5000) [5,22] . Experimental Results and Discussion
  • mice tumor models were established to examine whether immunity against antigens expressed on normal melanocytes and melanoma can lead to tumor rejection.
  • the brown locus product, gp75 was the target antigen in these models.
  • the gp75 autoantigen is relevant because it is potentially immunogenic in persons with melanoma, recognized on melanomas by both autoantibodies and autoreactive T cells [8,9] .
  • the mouse mAb TA99 binds to both human and mouse gp75, and reacts with normal melanocytes and melanoma but does not react with other tissues [22] .
  • TA99 mAb has been shown to localize efficiently to melanoma xenografts in mice (tumor:normal tissue ratios >100:1 to 10 5 :1) , showing that systemic administration of antibody against gp75 can specifically localize to tumor sites [23] .
  • the gp75 + B16F10 melanoma is a spontaneously arising tumor that is very weakly immunogenic in syngeneic
  • mice C57BL/6 mice.
  • B16F10 cells from fresh tumors express gp75 in melanosomes within the cell and on the cell surface (see Materials and Methods) .
  • Incubation of mAb TA99 (up to 600 mg/ml for seven days) with B16F10 melanoma cells in vi tro did not affect the cell growth, morphology or pigmentation.
  • Mice were challenged subcutaneously with B16F10 melanoma and treated with either mAb TA99 or isotype-matched control mAb UPC10. With this tumor challenge, B16F10 uniformly forms palpable tumors around two weeks. Tumors were rejected in mice treated with mAb TA99 but not in control mice
  • This anti-tumor effect was specific for tumors that expressed gp75 antigen. Tumor protection was seen for the gp75 + JBRH melanoma after subcutaneous challenge in syngeneic C57BL/6 mice (time to median appearance of tumors delayed by >31 days) . However, no antitumor effects were observed in syngeneic C57BL/6 mice with a gp75 " variant of the parental B16 melanoma (B78H.1 melanoma) , nor with other subcutaneous gp75 " tumors, including EL4 lymphoma, RMA lymphoma, Lewis lung carcinoma, or MC58 sarcoma.
  • Intravenous injection of B16F10 leads reproducibly to lung metastases [20,24] .
  • Treatment with mAb TA99 markedly reduced the number of lung surface metastases even at individual doses as low as 50 mg ( Figure 3A and data not shown) .
  • Injection of F(ab') 2 fragments of mAb TA99 did not have any effect on the number of B16F10 metastases, supporting a crucial role for the Fc portion of mAb TA99 in anti-tumor effects (data not shown) .
  • NKl.1 + cell population appeared to abrogate the protective effect of mAb TA99 in both metastatic B16F10 in the lung ( Figure 4) and subcutaneous B16F10 tumors (data not shown) , supporting a role for NK cells in tumor rejection mediated by mAb TA99.
  • NKl .1+ cells appear to provide natural immunity against B16F10 lung metastases [24] .
  • NKl.l NKl.l cells in the lung metastases model (using the same experimental design described in Figure 5 with 6-8 mice/group) : 1) Depletion of NKl .1+ cells from C57BL/6 mice led to a significant increase in the number of metastases (mean 314.+58 metastases) compared to control undepleted mice (136.+25 metastases) ; 2) Treatment with mAb TA99 markedly decreased metastases (12 ⁇ 11 metastases) ; and 3) The number of lung metastases in mice treated with mAb TA99 and also depleted of NKl .1 + cells was significantly greater (mean 186 ⁇ 42) than mice treated with TA99 alone (12 ⁇ 11) , but not as great as the number of metastases in untreated NKl.1-depleted mice (314 ⁇ 58) .
  • NKl.1 + cells binding mAb TA99 through Fc receptors secondarily activated CD4 * cells to participate in tumor rejection.
  • CD4 + T cells might be activated by antigen-presenting cells through internalization and presentation of antigen- antibody complexes.
  • mice treated with mAb TA99 were examined for changes in pigmentation and other autoimmune-type manifestations. The coat of animals remained black except if animals were depilated to prepare skin sites for tumor injection. Pigmented melanocytes on the trunk of adult mice are found in hair bulbs. Regenerating hairs on the trunk were depigmented in 13 of 13 tumor-bearing mice treated with mAb TA99 at 300-900 mg per dose (three times per week for two weeks) but not in mice treated with control mAb UPC10
  • mice (0 of 36 mice) or untreated control mice (0 of 30 mice) .
  • Depigmentation was not related to injection of tumor cells; treatment of depilated C57BL/6 mice without injection of tumor cells still led to depigmentation in 12 of 12 mice treated with 300-1000 mg dose of mAb TA99
  • mice There were no detectable alterations in behavior or weights of mice during or after treatment.
  • Thyl + cells were necessary for depigmentation, but NK1.1 + cells, complement, and the individual CD4 + or CD8 + T cell subsets were not necessary.
  • Applicants have shown that passive immunity against melanocytes can lead to effective rejection of even established tumors.
  • Melanoma is not the only tumor type where differentiation antigens are recognized by the immune system. Immune recognition of differentiation antigens has also been detected in patients with breast, colon, and pancreas carcinomas [30- 32] .
  • Human melanoma antigen AH is an autoantigenic ganglioside related to GD2. J. Exp. Med. 156: 1884-1889.
  • the melanoma antigen gp75 is the human homologue of the mouse b (brown) locus gene product . J. Exp. Med. 171: 1375-1380.

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Abstract

La présente invention décrit une composition pharmaceutique comprenant une quantité efficace d'anticorps monoclonal TA99 et un excipient acceptable sur le plan pharmaceutique. Elle décrit également une composition pharmaceutique comprenant une quantité efficace d'un anticorps TA99 humanisé et un excipient acceptable sur le plan pharmaceutique. Elle décrit aussi une composition pharmaceutique comprenant une quantité efficace d'un anticorps capable d'inhiber de manière compétitive la liaison de TA99 à gp75 et un excipient acceptable sur le plan pharmaceutique. Elle décrit encore un procédé pour traiter une tumeur, consistant à administrer une quantité efficace des compositions pharmaceutiques décrites ci-dessus. Dans un mode de réalisation, la tumeur est un mélanome.
PCT/US1996/010038 1995-06-07 1996-06-07 Usages therapeutiques du ta99 Ceased WO1996040249A1 (fr)

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AU61711/96A AU6171196A (en) 1995-06-07 1996-06-07 Therapeutic uses of ta99

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US08/479,774 1995-06-07

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7951370B2 (en) 2008-03-12 2011-05-31 Imclone Llc Anti-TYRP1 antibodies
WO2014201378A1 (fr) * 2013-06-13 2014-12-18 Massachusetts Institute Of Technology Traitement synergique de tumeur avec il-2 à pk prolongée et thérapie cellulaire adoptive
WO2015067710A3 (fr) * 2013-11-06 2015-06-25 Universite De Rennes 1 Tyrp1, un miarn "éponge" naturel, et son utilisation dans le cadre de la prise en charge de l'agressivité du mélanome chez l'être humain
US9844582B2 (en) 2012-05-22 2017-12-19 Massachusetts Institute Of Technology Synergistic tumor treatment with extended-PK IL-2 and therapeutic agents

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990007861A1 (fr) * 1988-12-28 1990-07-26 Protein Design Labs, Inc. IMMUNOGLOBULINES CHIMERIQUES SPECIFIQUES CONTRE LA PROTEINE TAC p55 DU RECEPTEUR D'IL-2

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990007861A1 (fr) * 1988-12-28 1990-07-26 Protein Design Labs, Inc. IMMUNOGLOBULINES CHIMERIQUES SPECIFIQUES CONTRE LA PROTEINE TAC p55 DU RECEPTEUR D'IL-2

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF INVESTIGATIVE DERMATOLOGY, Volume 90, issued 1988, THOMPSON et al., "Differentiation Antigens of Melanocytes and Melanoma: Analysis of Melanosome and Cell Surface Markers of Human Pigmented Cells with Monoclonal Antibodies", pages 459-466. *
PROC. NATL. ACAD. SCI. U.S.A., Volume 84, issued June 1987, WELT et al., "Monoclonal Antibody to an Intracellular Antigen Images Human Melanoma Transplants in Nu/Nu/Mice", pages 4200-4204. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7951370B2 (en) 2008-03-12 2011-05-31 Imclone Llc Anti-TYRP1 antibodies
US9844582B2 (en) 2012-05-22 2017-12-19 Massachusetts Institute Of Technology Synergistic tumor treatment with extended-PK IL-2 and therapeutic agents
WO2014201378A1 (fr) * 2013-06-13 2014-12-18 Massachusetts Institute Of Technology Traitement synergique de tumeur avec il-2 à pk prolongée et thérapie cellulaire adoptive
WO2015067710A3 (fr) * 2013-11-06 2015-06-25 Universite De Rennes 1 Tyrp1, un miarn "éponge" naturel, et son utilisation dans le cadre de la prise en charge de l'agressivité du mélanome chez l'être humain
US10287633B2 (en) 2013-11-06 2019-05-14 Universite De Rennes 1 TYRP1, a natural miRNA sponge, and its use in managing human melanoma aggressiveness

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