WO1992014491A1 - Immunotoxine tiree d'anticorps monoclonaux anti-cd5 - Google Patents

Immunotoxine tiree d'anticorps monoclonaux anti-cd5 Download PDF

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Publication number
WO1992014491A1
WO1992014491A1 PCT/EP1992/000338 EP9200338W WO9214491A1 WO 1992014491 A1 WO1992014491 A1 WO 1992014491A1 EP 9200338 W EP9200338 W EP 9200338W WO 9214491 A1 WO9214491 A1 WO 9214491A1
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WO
WIPO (PCT)
Prior art keywords
immunotoxin
toxin
antibody
momordin
iminothiolane
Prior art date
Application number
PCT/EP1992/000338
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English (en)
Inventor
Giuliana Porro
Daniela Modena
Fiorenzo Stirpe
Gianni Gromo
Original Assignee
Italfarmaco S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Italfarmaco S.P.A. filed Critical Italfarmaco S.P.A.
Publication of WO1992014491A1 publication Critical patent/WO1992014491A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • A61K47/6819—Plant toxins
    • A61K47/6825—Ribosomal inhibitory proteins, i.e. RIP-I or RIP-II, e.g. Pap, gelonin or dianthin

Definitions

  • the present invention relates to an immunotoxin obtained by covalent conjugation of a toxin of vegeta ⁇ ble origin to an anti-CD5 monoclonal antibody.
  • Toxins of vegetable origin inhibit protein synthe- sis in eukaryotic cells, thereby exerting a cytotoxic effect.
  • These substances comprise either a single poly- peptide chain with catalytic activity that inactivates ribosomes (ribosome inactivating protein Type 1, RIPl), or two chains, namely one with a catalytic function and one responsible for binding to the cell surface (RIP2).
  • the present invention provides immunotoxins the costituents of which are selected from ribosome inactivacting proteins (RIPss) Type 1 and anti-CD5 monoclonal antibodies, which are capable of recognising the surface antigen CD5 of human T lymphocytes (Reiter, C, Cluster report: CD5 in: Leukocyte Typing IV, ed.
  • the RIPl toxins used in the immunotoxins according to the present invention are of the saporin type, such as, for example, ⁇ aporin-6 (SO-6) (F. Stirpe et al. , Bioche . J. , 216, 433, 1983), briodin (F. Stirpe et al., Biochem. J. , 240, 659, 1986), briodin L (publication of European patent application 390,040), mo ordin (F. Stirpe et al., Biochem. J. , 186, 443, 1980), mo orcochin S (publication of European patent application 390,040), dianthins 30 and 32 (F. Stirpe et al., Biochem. J.
  • any single chain protein or glycoprotein vegetable toxin can be used in the immunoconjugates according to the present invention.
  • glycoprotein toxins can also be used in the corresponding partially or completely deglycosylated forms.
  • the CD5 antigen is a glycoprotein with a molecular weight of 67,000 D that is expressed by 90% of T lym ⁇ phocytes (Reinherz E.L. et al., J. Immunol. 123, 1312, 1989) and by 15% of B lymphocytes (Casali P. et al. , Immunol. Today !£, 364, 19). The latter belong to a particular subpopulation of B lymphocytes that produce multireactive antibodies that appear to be involved in the genesis of a number of autoimmune diseases. CD5. is also expressed in various acute B forms and chronic T and B forms of leukaemia and in a number of B lympho- mas.
  • the CD5 antigen therefore represents an ideal tar ⁇ get for anti-T lymphocyte antibodies.
  • Anti-T cell immu ⁇ notoxins in which the toxin portion is derived from ri ⁇ bosome inactivating proteins of vegetable origin have already been described, for example in US Patent No. 4,590,071.
  • the A chain of ricin - RIP Type 2 - is, in fact, the toxin that has been most widely studied with a view to preparing immunotoxins for therapeutic use.
  • the results of application obtained so far are not at all satisfactory, partly because of the unfavourable in vivo pharmacokinetics that are characteristic of immu- notoxins containing the A chain of ricin (J. Biol. Re ⁇ sponse Modifiers, ]_ > 559 «* 1988).
  • immunotoxins obtained by conjugating a known RIPl, preferably momordin, dianthin or PAP-S, to anti-CD5 monoclonal antibodies can be used advantageously in the ⁇ vivo or ex vivo treatment of conditions in which it ' is desirable to suppress T lymphocyte function, such as autoimmune- based diseases (rheumatoid arthritis) and Graft Versus Host Disease (GVHD) following a heterologous bone marrow transplant, or for the e_x vivo elimination from the bone marrow of leukaemic cells in the case of autologous transplants.
  • autoimmune- based diseases rheumatoid arthritis
  • GVHD Graft Versus Host Disease
  • the immunotoxi s according to the invention are prepared by conventional methods such as those descri ⁇ bed in EP-A-169,111 and in "Monoclonal Antibody - Toxin Conjugates: Aiming the Magic Bullet", Thorpe et al. Mo ⁇ noclonal Antibodies in Clinical Medicine, Academic Press, pp. 168-190 (1982).
  • a most preferred RIPl is momordin.
  • heterobifunctional reagents such as N-succinimidyl-3-(2-pyridyldithio)-propionate (SPDP) , 2-iminothiolane (Traut's reagent), S-acetylmercapto- succinic anhydride (SAMSA), carbodiimide, glutar ldehyde, etc. are used to conjugate the toxin to the antibody.
  • SPDP N-succinimidyl-3-(2-pyridyldithio)-propionate
  • 2-iminothiolane Traut's reagent
  • SAMSA S-acetylmercapto- succinic anhydride
  • carbodiimide glutar ldehyde, etc.
  • the monoclonal antibodies and the RIPl are pu ⁇ rified and prepared by conventional methods described briefly below.
  • the immunotoxins according to the invention will be formu- lated in pharmaceutical compositions suitable for pa ⁇ renteral (i. . and i.v.), topical and transdermal administration.
  • suitable solvents i. . and i.v.
  • the dosage will obviously depend on a number of factors such as the severity and type of disease, the general condition of the patient, and concomitant treatment, but in the majority of cases it will be between 0.01 mg/kg and 5 mg/kg, preferably between 0.01 mg/kg and 0.5 mg/kg.
  • the therapeutic regime can be based on one or two doses per day for periods of up to several weeks.
  • the results that can be obtained with the immuno- toxins according to the invention have the advantages of reduced non-specific toxicity compared with the known immunotoxins derived from ricin A, and more fa ⁇ vourable pharmacokinetics.
  • the cell line of hybridoma OKTl produces the mono- clonal antibody (MoAb) of class IgG,K, which recognises the lymphocytic antigen CD5.
  • MoAb mono- clonal antibody
  • This line acquired from the American Type Culture Collection (ATCC-CRL-8000) and redeposited on 1.10.1991 at the Institut Pasteur (1-1025) was expanded in culture using the standard methods (culture medium: RPMI 1640 containing 10% foe ⁇ tal bovine serum). To achieve a massive production cf antibody, 1-3 10 hybridoma cells were injected i.p.
  • the binding of the antibodies secreted in the cul ⁇ ture medium and in the ascitic fluid to positive CD5 cells was evaluated by a technique using indirect immunofluorescence, as described below (Fig. la, lb, lc).
  • the percentage of positive CD5 cells was between 72 and 75%.
  • the MoAb was purified from the ascitic fluid by affinity chromatography on protein A, followed by ad ⁇ sorption chromatography on hydroxyapatite.
  • Affinity chromatography (Ey P.L. et al., Immuno- chemistry L5_, 420, 1972): the ascitic fluid, removed sterilely, was clarified by centrifugation and filtered through nitrocellulose filters with a 0.45 ⁇ mesh. The filtrate, diluted 1:2 in the binding buffer (1.5M gly- cine, 3M NaCl, pH 9.8), was loaded into a column packed with Sepharose-protein A (Pharmacia).
  • the MoAb (IgG.
  • the purified MoAb was finally rendered pyrogen- free by affinity chromatography using a column packed with Detoxigel Endotoxin Removing Gel (Pierce), fol- lowing the supplier's instructions, in sterile condi ⁇ tions.
  • the level of endotoxins - less than 0.125 EU - was determined by the LAL test (Wittaker). All the solu ⁇ tions used in purifying the MoAb were prepared with apyrogenic water sterilised in an autoclave. The glas ⁇ sware was sterilised in the oven at 190°C and the re ⁇ sins were rendered pyrogen-free with NaOH or detergents according to the supplier's instructions.
  • the percentage of binding of the monoclonal anti- body produced by the OKTl cells was analysed in indi ⁇ rect immunofluorescence with flow cytofl orimetry on CD5 + cell lines (Jurkat) and mononuclear cells isolated from peripheral blood from healthy donors (PBMC) sepa ⁇ rated by density gradient (Ficoll-Pharmacia) .
  • the method described below was also used to deter ⁇ mine the binding of the antibody to the cell after conjugation to the toxin.
  • the momordin was purified from Momordica charantia seeds by the methods described earlier (Barbieri L. et al. , Biochem. J., 186, 443, 1980; Barbieri L. et al. , J. Chromatogr. 408, 235, 1987).
  • the purity of the momordin after chromatography on CM- Sepharose was estimated as >99% in SDS- PAGE.
  • the activity of the toxin was determined as inhi ⁇ bition of protein synthesis in an in. vitro translation system based on lysate of rabbit reticulocytes (Stirpe et al. , 3iochem. J. 240, 659, 1986).
  • the IC 50 value i.e. the concentration capable of inhibiting 50% of protein synthesis, obtained in the above system by measuring the incorporation of 14C-leu- cine into the proteins was 10 " M.
  • the conjugate was obtained from the chemical reac ⁇ tion between the anti-CD5 MoAb and momordin, both deri- vatised with 2-iminothiolane (2-IT) (Dinota A. et al. , Brit. J. Cancer , 315, 1989).
  • the first peak corre ⁇ sponded to a high molecular weight conjugate, the se- cond to a low molecular weight conjugate, followed by the trimers, di ers and monomers of the toxin.
  • the free Igs co-eluted with the final fraction of the low mole ⁇ cular weight conjugate as shown by the fact that the radioactivity peak did not coincide with (being smaller than) that of the absorption at 280 nm (Fig.2).
  • the low molecular weight fractions were combined and the momor ⁇ din:IgG ratio was calculated from the absorption at 280 nm and the cpm values of the peaks of low molecular weight conjugate and of momordin alone.
  • the purity of the conjugate was evaluated using indirect immunofluorescence as described earlier (Section 3). As shown in Fig. le, the conjugation left intact the ability of the MoAb to bind to CD5 + cells (73-78%) of labelled cells.
  • the biological activity was determined as inhibition of the incorporation of C- leucine into the proteins in a reticulocyte lysate sy ⁇ stem as described in Section 4.
  • the mean IC50 value was 10 " M. b) Inhibition of protein and DNA synthesis in PBMC (Stirpe F. et al., Br. J. Cancer _5_8, 558, 1988; Siena A. et al., Blood 7_2, 756, 1988)
  • the cells After being washed twice in physiological saline the cells were seeded in 96 well plates (50,000 cells/well in RPMI 1640 with the addition of 10% of fo ⁇ etal bovine serum and 10 ⁇ g/ml PHA (phytohaemagglu- tinin) (Wellcome) and incubated at 37 ⁇ C for 48 hours. After incubation for a further 15 hours in the presence of 1 ⁇ Ci/well of H-thymidine (to determine inhibition
  • the radioactivity incorporated by the cells was measured with the aid of a radioactivity counter (3- counter, LKB) and the IC50 of the various substances was determined by linear regression analysis.
  • mice Female nu/nu mice (Swiss background) were used; these already had reduced reactivity in the T compartment and were further immu- nosuppressed by means of 1) splenectomy, 2) irradiation (450 rads) 72 hours before being inoculated and 3) tre ⁇ atment, 24 hours before being inoculated, with a titra ⁇ ted solution of anti-asialoganglioside serum GMl to abolish the Natural Killer (NK) activity, which is gre- ater in athymic mice than in other urine strains.
  • NK Natural Killer
  • the animals were treated 9 times (twice a week) and any antileukaemic effect was evaluated in terms of inhibition of the growth of the tumour mass and the change in the numbers of animals reaching the latency threshold (time taken for the tumour nodule to develop) and surival threshold (time taken for the tu ⁇ mour to bring about death) .

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Abstract

L'invention concerne une immunotoxine pouvant être obtenue par conjugaison covalente d'une protéine de type 1 d'inactivation de ribosome avec un anticorps monoclonal anti-CD5.
PCT/EP1992/000338 1991-02-26 1992-02-18 Immunotoxine tiree d'anticorps monoclonaux anti-cd5 WO1992014491A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI910491A IT1249051B (it) 1991-02-26 1991-02-26 Immunotossina da anticorpi monoclonali anti-cd5
ITM191A000491 1991-02-26

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5621083A (en) * 1991-11-04 1997-04-15 Xoma Corporation Immunotoxins comprising ribosome-inactivating proteins
US5837491A (en) * 1991-11-04 1998-11-17 Xoma Corporation Polynucleotides encoding gelonin sequences
US6146850A (en) * 1991-11-04 2000-11-14 Xoma Corporation Proteins encoding gelonin sequences
CN111670052A (zh) * 2017-11-29 2020-09-15 美真达治疗公司 用于耗尽cd5+细胞的组合物和方法
WO2020216947A1 (fr) 2019-04-24 2020-10-29 Heidelberg Pharma Research Gmbh Conjugués anticorps-médicaments d'amatoxine et leurs utilisations

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0017381A2 (fr) * 1979-03-20 1980-10-15 Ortho Pharmaceutical Corporation Anticorps monoclônal contre les cellules T humaines, procédé pour sa préparation, lignée cellulaire hybride le produisant, composition thérapeutique le contenant et méthode de diagnostic l'utilisant
EP0192002A1 (fr) * 1985-02-13 1986-08-27 Elf Sanofi Immunotoxines à longue durée d'action comportant un constituant glycopeptique inactivant les ribosomes modifié sur ses motifs polysaccharidiques
WO1986005098A1 (fr) * 1985-03-04 1986-09-12 Dana-Farber Cancer Institute, Inc. Immunotoxine et procede de production
US4831122A (en) * 1986-01-09 1989-05-16 Regents Of The University Of Minnesota Radioimmunotoxins
WO1989006967A1 (fr) * 1988-02-03 1989-08-10 Xoma Corporation Immunosuppresion a l'aide de compositions d'immunotoxines de cellules t anti-pan
WO1989006968A1 (fr) * 1988-02-03 1989-08-10 Xoma Corporation Utilisation therapeutique d'immunotoxiques anti-cellules t contre des maladies autoimmunes
WO1989011871A1 (fr) * 1988-06-01 1989-12-14 Cetus Corporation Purification chromatographique de conjugues d'immunotoxines a une etape utilisant une matrice thiophilique

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0017381A2 (fr) * 1979-03-20 1980-10-15 Ortho Pharmaceutical Corporation Anticorps monoclônal contre les cellules T humaines, procédé pour sa préparation, lignée cellulaire hybride le produisant, composition thérapeutique le contenant et méthode de diagnostic l'utilisant
EP0192002A1 (fr) * 1985-02-13 1986-08-27 Elf Sanofi Immunotoxines à longue durée d'action comportant un constituant glycopeptique inactivant les ribosomes modifié sur ses motifs polysaccharidiques
WO1986005098A1 (fr) * 1985-03-04 1986-09-12 Dana-Farber Cancer Institute, Inc. Immunotoxine et procede de production
US4831122A (en) * 1986-01-09 1989-05-16 Regents Of The University Of Minnesota Radioimmunotoxins
WO1989006967A1 (fr) * 1988-02-03 1989-08-10 Xoma Corporation Immunosuppresion a l'aide de compositions d'immunotoxines de cellules t anti-pan
WO1989006968A1 (fr) * 1988-02-03 1989-08-10 Xoma Corporation Utilisation therapeutique d'immunotoxiques anti-cellules t contre des maladies autoimmunes
WO1989011871A1 (fr) * 1988-06-01 1989-12-14 Cetus Corporation Purification chromatographique de conjugues d'immunotoxines a une etape utilisant une matrice thiophilique

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Blood, vol. 72, no. 2, August 1988, (New York, US), S. SIENA et al.: "Synthesis and characterization of an antihuman T-lymphocyte saporin immunotoxin (OKTI-SAP) with in vivo stability into nonhuman primates", pages 756-765, see the whole article (cited in the application) *
Br. J. Cancer, vol. 58, 1988, (London, GB), F. STIRPE et al.: "Selective cytotoxic activity of immonotoxins composed of a monoclonal anti-Thy 1.1 antibody and the ribosome-inactivating proteins bryodin and momordin", pages 558-561, see the whole article (cited in the application) *
Cancer Research, vol. 49, 15 June 1989, (Philadelphia, PA, US), S. SIENA et al.: "Immunotoxin-mediated inhibition of chronic lymphocytic leukemia cell proliferation in humans", pages 3328-3332, see page 3328, abstract; page 3329, paragraphs 3,4 *
European Journal of Haematology (Proceedings of the International Conference on Multiple Myeloma, Biology, pathophysiology, prognosis and treatment, Bologna, 19-22 June 1989), vol. 43, no. 51, 1989, F. STIRPE et al.: "Ex vivo bone marrow purging with immunotoxins", pages 173-175, see the whole article *
Xenobiotica, vol. 20, no. 12, 1990, (London, GB), L. BARBIERI et al.: "Blood clearance and organ distribution and tissue concentration of native, homopolymerized and IgG-conjugated ribosome-inactivating proteins", pages 1331-1341, see page 1333, table 1; page 1334, paragraphs 4-9 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5621083A (en) * 1991-11-04 1997-04-15 Xoma Corporation Immunotoxins comprising ribosome-inactivating proteins
US5744580A (en) * 1991-11-04 1998-04-28 Xoma Corporation Immunotoxins comprising ribosome-inactivating proteins
US5756699A (en) * 1991-11-04 1998-05-26 Xoma Corporation Immunotoxins comprising ribosome-inactivating proteins
US5837491A (en) * 1991-11-04 1998-11-17 Xoma Corporation Polynucleotides encoding gelonin sequences
US6146850A (en) * 1991-11-04 2000-11-14 Xoma Corporation Proteins encoding gelonin sequences
US6146631A (en) * 1991-11-04 2000-11-14 Xoma Corporation Immunotoxins comprising ribosome-inactivating proteins
US6376217B1 (en) 1991-11-04 2002-04-23 Xoma Technology Ltd. Fusion proteins and polynucleotides encoding gelonin sequences
US6649742B1 (en) 1991-11-04 2003-11-18 Xoma Technology Ltd. Immunotoxins comprising ribosome-inactivating proteins
CN111670052A (zh) * 2017-11-29 2020-09-15 美真达治疗公司 用于耗尽cd5+细胞的组合物和方法
WO2020216947A1 (fr) 2019-04-24 2020-10-29 Heidelberg Pharma Research Gmbh Conjugués anticorps-médicaments d'amatoxine et leurs utilisations

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AU1208892A (en) 1992-09-15
ITMI910491A0 (it) 1991-02-26
ITMI910491A1 (it) 1992-08-26
EP0577612A1 (fr) 1994-01-12
IT1249051B (it) 1995-02-11

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