EP0614377A1 - Procede de diagnostic et de traitement du cancer - Google Patents

Procede de diagnostic et de traitement du cancer

Info

Publication number
EP0614377A1
EP0614377A1 EP93900522A EP93900522A EP0614377A1 EP 0614377 A1 EP0614377 A1 EP 0614377A1 EP 93900522 A EP93900522 A EP 93900522A EP 93900522 A EP93900522 A EP 93900522A EP 0614377 A1 EP0614377 A1 EP 0614377A1
Authority
EP
European Patent Office
Prior art keywords
growth factor
conjugate
cancer
animal
administering
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP93900522A
Other languages
German (de)
English (en)
Inventor
Frederick C. Leung
Darrell R. Fisher
Michael R. Thompson
Scott D. Harvey
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Battelle Memorial Institute Inc
Original Assignee
Battelle Memorial Institute Inc
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 Battelle Memorial Institute Inc filed Critical Battelle Memorial Institute Inc
Publication of EP0614377A1 publication Critical patent/EP0614377A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention provides reagents and methods for detecting and treating cancer.
  • a conjugate of a growth factor and an alpha-emitting radionuclide is provided, the growth factor being capable of specifically binding to a defined population of cancer cells.
  • the growth factor is coupled to the alpha-emitting radionuclide by a linker, such as a short polycarbon compound, to separate the alpha-emitting radionuclide from the growth factor.
  • a linker such as a short polycarbon compound
  • Preferred linkers may be selected from the group consisting of disulfides, dicarboxylic acids, and multi- carbon chain linkers (polycarbons).
  • a particularly preferred linker is hexamethylene diamine.
  • FIGURE 4 is a graph which compares cells treated with 3 I, 131 I- epidermal growth factor, and epidermal growth factor alone.
  • FIGURE 5 is a graph which illustrates the effects of various concentrations of - ⁇ --I-epide ⁇ nal growth factor on A431 cells.
  • FIGURE 6 is a graph which illustrates the effects of various concentrations of 131 I-epidermal growth factor on L cells.
  • separation of the complexed and free radionuclide can be accomplished by partitioning between an organic solvent (such as chloroform) and water.
  • the complexed radionuclide will partition into the organic phase, whereas the free radionuclide will reside exclusively in the aqueous phase.
  • chromatographic techniques such as High Performance Liquid Chromatography (HPLC) or Reverse-Phase High Performance Liquid Chromatography (RP-HPLC) may be utilized to separate sequestered radionuclide from the free cation. Once isolated, verification of the molecular architecture may be accomplished.
  • the alpha-emitting radionuclide is positioned within a sequestering agent which is i turn coupled by a linker to preferably either the amino ("N") or carboxy ("C") terminus of the growth factor.
  • the linker serves to place an inert "spacer" between the biologically active growth factor and the alpha-emitting radionuclide containing complex. This space minimizes steric interactions that may interfere with the growth factor's affinity towards its target.
  • the optimum length of the spacer arm is primarily dependent on the affinity of the growth factor for its target receptor. The higher this affinity, the smaller the relative importance of stearic repulsion between the sequestering agent and the target receptors.
  • linkers may be selected which are suitable for use within the present invention, although presently preferred linkers include disulfides, dicarboxylic acids, polycarbon chains, and modified polycarbon chains. Preferred linkers include hydrocarbon chains which range in length from 4 to 18 carbon atoms. Particularly preferred linkers have at least she methylene units such as hexamethylene diamine.
  • the linker may be attached to any of a number of extraanular functionalities on the sequestering agent, although carboxy and amino functionalities are particularly preferred.
  • a first synthetic step could involve reaction of the sequestering agent with hexamethylene diamine. Subsequent reaction with the C-terminus of the growth factor would complete synthesis of the conjugate.
  • the linker may be coupled to other aspects of the growth factor such as the N-terminus.
  • the sequestering agent may be reacted with succinic anhydride. Subsequent coupling of the linker to the growth factor may then be accomplished through the N-terminus of the growth factor.
  • an appropriate functionality is inserted into the sequestering agent.
  • a bromine atom may be incorporated into the appropriate position of an aromatic constituent during synthesis of the macrocyclic compound (see Skowronska-Ptasinska et al., J. Org. Chem 53:5484-91, 1988). Sequential treatment of this compound with n- butyllithium and CO2 yields the carboxy analog:
  • the sequestering agent is not immobilized on a rigid support the following by-product may also be produced:
  • Solubility incompatibilities may be overcome by use of a 50:50 dimethylformamide:water solvent system (see generally Cooper, The Tools of Biochemistry, Wiley, New York, pp. 234-255, 1977; Cuatrecasas, "Protein Purification by Affinity Chromatography on Polyacrylamide Beads,” J Biol. Chem. 245:3059, 1970; and Cuatrecasas, "Affinity Chromatography of Macromolecules," in Advances in Enzymology, A. Meister (ed.), Wiley, New York, p.29, 1972).
  • the growth factor is conjugated to non-radioactive iodine.
  • the present invention provides, prior to the step of administering an effective amount of a conjugate as described above, administering an unlabeled growth factor capable of specifically binding to the defined population of cancer cells, in an amount sufficient to mask growth factor receptors in healthy tissues of the animal.
  • administering an unlabeled growth factor capable of specifically binding to the defined population of cancer cells in an amount sufficient to mask growth factor receptors in healthy tissues of the animal.
  • administration of the conjugated growth factor is preceded by the step of administering a "cold" or unlabeled growth factor capable of binding to growth factor receptors in both normal and cancer cells, thereby reducing the number of receptor sites on normal cells available for binding and thus minimizing radiation damage to normal cells.
  • Masking of growth factor receptors may be accomplished in methods for both treating and diagnosing cancer, as described herein.
  • a method for diagnosing and treating cancer in warm-blooded animals comprising the steps of (a) administering to the animal an unlabeled growth factor capable of specifically binding to a defined population of cancer cells, in an amount sufficient to mask growth factor receptor sites in healthy tissues of the animal, (b) administering to the animal an effective amount of a first conjugate of a growth factor and a radioactive isotope which emits gamma radiation, (c) detecting the presence and location of the conjugate within the warm-blooded animal and therefrom determining the presence of the cancer, and (d) administering an effective amount of a second conjugate of a growth factor and a cytotoxic metal ion, such that the cancer is treated.
  • the cytotoxic agent is an alpha particle emitting radioactive isotope selected from the group consisting of lead-
  • the human cervical epidermoid carcinoma cell line A431 (available from the American Type Culture Collection or "ATCC,” Rockville, Maryland, under accession number CRL 1555) was grown in Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum. The cells were harvested by trypsinization with 0.05% trypsin and counted with trypan blue to obtain the number of live cells. A431 cells have approximately 1-2 x 10 6 EGF receptors per cell.
  • FIG. 3 shows that the wells of A431 cells exposed to 131 I-EGF have significantly fewer viable cells as compared to cells exposed to free 131 I or cells exposed to unlabeled EGF.
  • radiolabeled growth factor can be used as a specific cytotoxic agent for human tumor cells which possess high numbers of the growth factor receptor.
  • mice injected subcutaneously into nude mice.
  • the cells were allowed to grow in the mice for one to two weeks, after which the mice were injected either with or without unlabeled EGF, followed by the injection of 123 I-EGF.
  • the mice were then sacrificed and the percent of injected dose per gram determined in the blood, tumor, muscle, lung, kidney, spleen, liver, intestine, thyroid, urine and stomach. The results of this experiment are set forth below in Tables I and II.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention décrit des conjugués de facteurs de croissance et de radionucléides alphaémetteurs appropriés pour détecter et traiter le cancer. On décrit également des procédés de traitement du cancer utilisant des conjugués de facteurs de croissance et d'iode non radioactif, des conjugués de facteurs de croissance et d'un oxyanion d'un métal, et des conjugués d'un facteur de croissance et d'un isotope radioactif.
EP93900522A 1991-11-14 1992-11-16 Procede de diagnostic et de traitement du cancer Withdrawn EP0614377A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US79218191A 1991-11-14 1991-11-14
US792181 1991-11-14
PCT/US1992/009874 WO1993009816A1 (fr) 1991-11-14 1992-11-16 Procede de diagnostic et de traitement du cancer

Publications (1)

Publication Number Publication Date
EP0614377A1 true EP0614377A1 (fr) 1994-09-14

Family

ID=25156052

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93900522A Withdrawn EP0614377A1 (fr) 1991-11-14 1992-11-16 Procede de diagnostic et de traitement du cancer

Country Status (5)

Country Link
EP (1) EP0614377A1 (fr)
JP (1) JPH07501332A (fr)
AU (1) AU3177893A (fr)
CA (1) CA2123588A1 (fr)
WO (1) WO1993009816A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2179990A1 (fr) * 1994-01-12 1995-07-20 Gary Robert Bower Agents biologiques de ciblage
NO310544B1 (no) * 1999-01-04 2001-07-23 Algeta As Opparbeidelse og anvendelse av radium-223 til fremstilling av preparat samt kit til behandling av kalsifisert vev for palliasjon, benkreft-terapi og/eller overflatebehandling av ben
KR20070106731A (ko) * 2005-02-22 2007-11-05 지이 헬쓰케어 리미티드 방사성표지된 갈륨 복합체, 그의 합성방법 및 악성종양에서 ｅｇｆｒ 발현의 ｐｅｔ 영상화를 위한 그의 용도
US20100316639A1 (en) 2009-06-16 2010-12-16 Genentech, Inc. Biomarkers for igf-1r inhibitor therapy
GB201007354D0 (en) * 2010-04-30 2010-06-16 Algeta Asa Method
CN109152845B (zh) * 2016-04-14 2022-07-12 宝力泰锐克斯有限公司 含有在环内包含至少两个(-ch2-ch2-o-)单元的接头的缀合物和缀合试剂
US11798700B2 (en) 2018-03-26 2023-10-24 The University Of British Columbia Systems, apparatus and methods for separating actinium, radium, and thorium

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5037630A (en) * 1985-01-14 1991-08-06 Neorx Corporation Metal radionuclide labeled proteins for diagnosis and therapy
US5059541A (en) * 1988-04-29 1991-10-22 Neorx Corporation Minimal derivatization of proteins
US4988496A (en) * 1988-05-31 1991-01-29 Neorx Corporation Metal radionuclide chelating compounds for improved chelation kinetics
US5135736A (en) * 1988-08-15 1992-08-04 Neorx Corporation Covalently-linked complexes and methods for enhanced cytotoxicity and imaging
DK0436005T3 (da) * 1989-07-20 1995-07-03 Sandoz Ltd Mærkede polypeptidderivater

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9309816A1 *

Also Published As

Publication number Publication date
CA2123588A1 (fr) 1993-05-27
AU3177893A (en) 1993-06-15
WO1993009816A1 (fr) 1993-05-27
JPH07501332A (ja) 1995-02-09

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