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Method and composition for the treatment of cancer by the enzymatic conversion of soluble radioactive toxic agents into radioactive toxic precipitates in the cancer

  • US 6,080,383 A
  • Filed: 01/13/1997
  • Issued: 06/27/2000
  • Est. Priority Date: 01/13/1997
  • Status: Expired due to Fees
First Claim
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1. A method for treating a heterogeneous population of cancer cells in a living host by at least a first therapeutic agent and an additional therapeutic agent, the living host being a natural system composed of extra-cellular fluid and normal cells and cancer cells growing in the extra-cellular fluid, the normal cells containing soluble and cellular components which can attack and kill cancer cells, the normal cells growing in a normal extra-cellular matrix, the normal extra-cellular matrix having at least collagen and fibronectin, the heteragenous population of cancer cells growing in a cancer-altered extra-cellular matrix having at least cancer-altered antigenic epitopes, the heterogeneous population of cancer cells endogenously making and containing products selected from the group consisting of sulphated glycosaminoglycans, natural intra-cellular enzymes in the natural enzyme-rich vacuoles contained in the cell which are lysosomes, and natural intra-cellular material selected from the group consisting of DNA, histone and complexes of DNA-histone, the DNA, histone and complexes of DNA-histone having antigenic epitopes, the heterogeneous population of cancer cells selected from the group consisting of least three sub-populations of cancer cells:

  • a first sub-population of cancer cells being first target cancer cells each having a first antigenic receptor which is substantially specific to a cancer cell and which binds a first targeting agent, the first antigenic receptor inducing endocytosis when the first targeting agent binds to the first antigenic receptor;

    the first target cancer cells having a sensitivity to being killed by the natural system of the living host and a sensitivity to being killed by the first therapeutic agent; and

    a second sub-population of cancer cells being second target cancer cells each having a third antigenic receptor which is substantially specific to a cancer cell and which binds a third targeting agent, the third antigenic receptor being incapable of endocytosis; and

    a third sub-population of cancer cells being non-target cancer cells which are the remainer of the cancer cells;

    the normal cells of the living host endogenously making and containing products selected from the group consisting of sulphated glycosaminoglycans, natural intra-cellular enzymes in their lysosomes, and natural intra-cellular material selected from the group consisting of DNA, histone and complexes of DNA-histone, the DNA, histone and complexes of DNA-histone having antigenic epitopes, the normal cells selected from the group consisting of two sub-populations of normal cells;

    a first sub-population of normal cells having first target normal cells which also have the first antigenic receptor and further having a sensitivity to being killed by the natural system of the living host and a sensitivity to being killed by the first therapeutic agent, the first target normal cells further having a second antigenic receptor which is substantially specific to normal cells and which binds a second targeting agent, the second antigenic receptor being induced to endocytose when the second targeting agent binds to the second antigenic receptor; and

    the second sub-population of normal cells having non-target normal cells which are the remainder of the normal cells;

    the method comprising the steps of;

    administering to the living host a therapeutic effective amount of a soluble binary reagent including the first targeting agent which has substantial affinity for the first antigenic receptors, the binary reagent further including a soluble precipitable material which is attached to the first targeting agent;

    allowing the soluble binary reagent to be endocytosed into the lysosomes of the first target cancer cells and into the lysosomes of the first target normal cells, the endocytosing and the natural intra-cellular enzymes in the lysosomes of the cells causing the soluble precipitable material to detach from the first targeting agent and thereby enabling the soluble precipitable material, upon being detached, to from a precipitate which has at least one of a first antigenic epitope being an epitope which is an integral part of the precipitate, a second antigenic epitope, and a neo-antigenic third epitope, the precipitate accumulating in the lysosomes within the first target cancer cells and within the first target normal cells;

    continuing the administering of the soluble binary reagent into the living host to increase the accumulation of the precipitate in the first target cancer cells and in the first target normal cells to form a quantity of antigenic epitopes which is proportional to the amount of accumulation of the precipitate;

    administering to the living host a therapeutic effective amount of the first therapeutic agent which causes a cell-killing process which kills the first target cancer cells and the first target normal cells and thereby causing the accumulation of the precipitate having the quantity of antigenic epitopes to be relocated into the extra-cellular fluid adjacent to the first target cancer cells and to the first target normal cells, the relocated precipitate now becoming a first extra-cellular precipitate having the quantity of antigenic epitopes, the cell killing process further causing the relocation of the natural intra-cellular material having antigenic epitopes to the extra-cellular fluid adjacent to the first target cancer cells and the first target normal cells;

    administering to the living host a therapeutic effective amount of a bispecific reagent including a non-mammalian enzyme moiety, the bispecific reagent further including a targeting agent moiety having substantial affinity for one of the first antigenic epitope, the second antigenic epitope, and the neo-antigenic third epitope of the first extra-cellular precipitate, the bispecific reagent being received and bound at the first extra-cellular precipitate, the first extra-cellular precipitate being retained in the extra-cellular fluid for a period of time, which enables the non-mammalian enzyme moiety to convert an amount of an additional therapeutic agent into a new form adapted to remain adjacent to the first extra-cellular precipitate for a period of time sufficient to kill non-selectively all cells adjacent to the first extra-cellular precipitate; and

    administering to a living host a therapeutic effective amount of the additional therapeutic agent which is a soluble radioactive toxic agent to be converted by the non-mammalian enzyme moiety into a new form which remains adjacent to the first extra-cellular precipitate for a period of time sufficient to kill non-selectively all cells adjacent to the first extra-cellular precipitate.

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