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Immunotoxins directed against malignant cells

a technology of immunotoxins and malignant cells, applied in the direction of antibody medical ingredients, peptide/protein ingredients, peptide sources, etc., can solve the problems of stymied utilization of this type of anti-tumor therapy, undesired side effects, and traditional chemotherapies, and achieve dramatic lowering of side effects and surprising properties

Inactive Publication Date: 2005-11-10
THE GOVT OF THE U S A AS REPRESENTED BY THE SECT OF THE DEPT OF HEALTH & HUMAN SERVICES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] We have found that these particular immunotoxins had highly surprising properties as they were up to 2000 fold more active against malignant B cells than their human RNase counterparts or than the toxin itself Further, as will be described in more detail below, their use when administered in vivo against disseminated tumors, resulted in dramatically lowered side effects. These highly effective, but apparently non-toxic, immunotoxins directed against such ubiquitous diseases as B cell lymphomas present a new and exciting therapeutic option for patients suffering from such diseases.

Problems solved by technology

Traditional chemotherapies, while being effective in the treatment of some cancerous conditions, exhibit undesired side effects due to the systemic toxicity of the chemotherapeutic compounds.
Utilization of this type of anti-tumor therapy, however, has been stymied by the development of immune responses in patients to foreign proteins which comprise the immunotoxins.
However, no solution has been found to counter the immunogenicity of the toxic moiety other than immunosuppression of the patients (Khazaeli, et al., Proceedings of AACR 29:418 (1988)).

Method used

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  • Immunotoxins directed against malignant cells
  • Immunotoxins directed against malignant cells
  • Immunotoxins directed against malignant cells

Examples

Experimental program
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Effect test

example 1

Production of Native and Recombinant Onc Protein from Rana pipiens

[0093] A. Isolation and Purification of Native Onc Protein

[0094] Techniques describing the isolation of oocytes from Rana pipiens, in vitro fertilization of the eggs, and the isolation and purification of native onc protein from frog embryos are exquisitely detailed in U.S. Pat. Nos. 5,559,212 and 5,728,805, which are both incorporated by reference herein.

[0095] B. Production and Assaying of Recombinant Onc Protein

[0096] The production of recombinant onc protein was done as described in PCT application PCT / US97 / 02588. Ribonucleolytic activity using high molecular weight RNA and tRNA was determined following published protocols, Newton, et al., J. Neurosci. 14:538 (1994) at 37° C. through the formation of perchloric acid soluble nucleotides (see, Newton, et al., Biochem. 35:545 (1996)). With poly (A,C), UpG, and poly U, ribonuclease activity was assayed spectrophotometrically according to Libonati, et al., Biochim....

example 2

Chemical Analysis and Composition of Onc Proteins

[0097] The native onc protein described above has been well characterized chemically. To be as fully functional as the native onc protein, it is believed the recombinant onc protein should have the chemistry and structure as described below.

[0098] The native onc protein was purified to homogeneity (as established by standard tests used to assay the homogeneity of proteins). By electrophoresis, the molecular weight of the native onc protein was determined to be approximately 14,500 Daltons. Calculation of the molecular weight based upon the listed amino acid sequence (see, infra), indicated the molecular weight of native onc protein should be 11,860 Daltons. However, because metal ions may have bonded to the protein despite all efforts to remove them, and because different isotopes may be involved, the molecular weight of the native onc protein was 12,430 Daltons as determined by mass spectroscopy. In view of this discrepancy, the mo...

example 3

ANTI-CD22-ONCONASE® Immunotoxin

[0102] A. Materials and Methods

[0103] ONCONASE® (previously named P-30) was provided by Alfacell Corp. as a lyophilized protein and was dissolved in phosphate buffered saline (PBS). Stock solutions of at least 1 mg / mL were kept frozen at −20° C. until dilutions were prepared for assays. All other reagents were purchased from sources previously described (Rybak, et al., J. Biol. Chem. 266:21202 (1991); Newton, et al., J. Biol. Chem. 267:19572 (1992); Mikulski, et al., Cell Tissue Kinet. 23:237 (1990)), herein incorporated by reference.

[0104] LL2 is a murine monoclonal antibody that recognizes and specifically binds to CD22 on human B cells. The LL2 antibody was provided by Immunomedics, Inc. (Morris Plains, N.J.). RFB4 is also a murine monoclonal antibody that binds to CD22. This antibody is available from many sources, including Ancell Corp.

[0105] Three Burkitt lymphoma cell lines (Daudi (ATCC CCL 213), CA 46 (ATCC CRL 1648), and Raji (ATCC CCL86))...

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Abstract

The present invention relates to immunotoxins, that effectively kill malignant cells having a given surface marker and nucleic acid constructs encoding them. These reagents comprise a toxic moiety that is derived from a Rana pipiens protein having ribonucleolytic activity linked to an antibody capable of specific binding with a chosen tumor cell.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of and claims priority to U.S. Provisional Application 60 / 046,895, filed May 2, 1997. The disclosure of the following U.S. Provisional Patent Application is incorporated herein by reference in its entirety: S. M. Rybak and D. L. Newton, “Recombinant Anti-Tumor RNAse,” filed Mar. 27, 1998 (Attorney Docket No. 15280-343000).FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] Not applicable. BACKGROUND OF THE INVENTION [0003] Toxic enzymes from plants and bacteria such as ricin, diphtheria toxin and Pseudomonas toxin have been coupled to antibodies or receptor binding ligands to generate cell-type-specific-killing reagents (Youle, et al., Proc. Nat'l Acad. Sci. USA 77:5483 (1980); Gilliland, et al., Proc. Nat'l Acad. Sci. USA 77:4539 (1980); Krolick, et al., Proc. Nat'l Acad. Sci. USA 77:5419 (1980)). Regardless of the fact that the cell-recognition moiety is not always an antibody, these directed toxins a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/00A61K38/43A61K39/395C12N15/09A61K47/48A61P35/00A61P35/02A61P43/00C07K14/46C07K16/28C07K16/30C07K16/46C07K19/00C12N9/22C12Q1/34
CPCA61K38/00A61K47/48438A61K47/48561C07K2319/00C07K16/2803C07K16/2833C07K16/3061C07K14/463A61K47/6817A61K47/6849A61P35/00A61P35/02A61P43/00
Inventor GOLDENBERG, DAVIDRYBAK, SUSANNANEWTON, DIANNE
Owner THE GOVT OF THE U S A AS REPRESENTED BY THE SECT OF THE DEPT OF HEALTH & HUMAN SERVICES
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