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Antibody and antibody fragments for inhibiting the growth of tumors

a technology of antibody fragments and tumors, applied in the field of antibodies and antibody fragments, can solve the problems of increased cost and effort, poor prognosis of amplification and/or overexpression of the egf receptors on the membranes of tumor cells, and the possibility of human anti-mouse antibody (hama) response, and achieve the effect of statistically significant reduction of the overall tumor volum

Inactive Publication Date: 2007-05-24
GOLDSTEIN NEIL I +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The patent describes a new polypeptide that lacks parts of an antibody and can be used to inhibit the growth of tumor cells. This polypeptide can be attached to other molecules that can also inhibit tumor growth, such as chemotherapy drugs. The polypeptide can be administered to humans to treat tumor cells that express a specific receptor. The technical effect of this invention is to provide a new tool for treating tumor cells that is targeted and effective."

Problems solved by technology

The amplification and / or overexpression of the EGF receptors on the membranes of tumor cells is associated with a poor prognosis.
A disadvantage of using murine monoclonal antibodies in human therapy is the possibility of a human anti-mouse antibody (HAMA) response due to the presence of mouse Ig sequences.
Unfortunately, both the cost and effort increase as more regions of a murine antibodies are replaced by human sequences.
Aboud-Pirak et al. found that both the antibody and the bivalent F(ab′)2 fragment retarded tumor growth in vivo, although the F(ab′)2 fragment was less efficient.

Method used

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  • Antibody and antibody fragments for inhibiting the growth of tumors
  • Antibody and antibody fragments for inhibiting the growth of tumors
  • Antibody and antibody fragments for inhibiting the growth of tumors

Examples

Experimental program
Comparison scheme
Effect test

example i

Materials

Example I-1

Cell Lines and Media

[0073] A431 cells were routinely grown in a 1:1 mixture of Dulbecco's modified Eagle's medium and Ham's F-12 supplemented with 10% fetal bovine serun, 2 mM L-glutamine, and antibiotics.

[0074] The androgen-independent and dependent human prostatic carcinoma cell lines (DU 145, PC-3 and LNaP) were obtained from the ATCC (Rockville Md.) and routinely maintained in RPMI 1640 medium (Sigma, St. Louis, Mo.) supplemented with 10% fetal bovine serum (Intergen, Purchase N.Y.) and 2 mM L-glutamine (Sigma). Cells were checked regularly for the presence of mycoplasma.

example i-2

Preparation and Purification of M225 and C225

[0075] The 225 antibody was grown as ascites in pristane primed Balb / c mice. Ascites fluid was purified by HPLC (ABX and Protein G) and determined to be >95% pure by SDS PAGE.

[0076] Human clinical grade C225 was grown in proprietary serum free medium in 300 liter lots. After clarification, the concentrated broth was purified on a series of chromatographic columns and vialed under asceptic conditions. Purity was determined to be >99% by SDS PAGE.

example i-3

Preparation of Doxorubicin-C225 Conjugates

[0077] C225 doxorubicin conjugates (C225-DOX) were prepared using a modification of the method described by Greenfield et al., Cancer Research 50, 6600-6607 (1990). Briefly, Doxorubicin was reacted with the crosslinking agent PDPH (3-[2-pyridyldithio]propionyl hydrazide) (Pierce Chemical Co.) to form the acyl hydrazone derivative doxorubicin 13-[3-(2-pyridyldithiol) propionyl) hydrazone hydrochloride. C225 was thiolated with the reagent N-succinimydyl 3-(pyridyldithio) propionate and reacted with doxorubicin hydrazone to form a conjugate containing a hydrazide as well as a disulfide bond. The complex was purified by gel filtration at neutral pH. The C225-doxorubicin conjugate was stable at neutral to alkaline pH (pH 7-8) and was stored at 4 C. The conjugate was readily hydrolyzed at pH 6, releasing active Doxorubicin.

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Abstract

Chimerized and humanized versions of anti EGF receptor antibody 225 and fragments thereof for treatment of tumors.

Description

[0001] This application is a continuation-in-part of Ser. No. 08 / 573,289 filed Dec. 15, 1995, which was a continuation-in-part of Ser. No. 08 / 482,982 filed Jun. 7, 1995, the disclosures of both of which are incorporated herein by reference.FIELD OF THE INVENTION [0002] The present invention is directed to antibodies and antibody fragments useful in inhibiting the growth of certain tumor cells. BACKGROUND OF THE INVENTION [0003] Recent research has uncovered the important role of growth factor receptor tyrosine kinases in the etiology and progression of human malignancies. These biological receptors are anchored by means of a transmembrane domain in the membranes of cells that express them. An extracellular domain binds to a growth factor. The binding of the growth factor to the extracellular domain results in a signal being transmitted to the intracellular kinase domain. The transduction of this signal contributes to the events that are responsible for the proliferation and differen...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07H21/04C12P21/06C12N5/06C07K16/30C07K16/46A61K33/24A61K38/00C07K16/28
CPCA61K38/00A61K2039/505C07K16/2863C07K2317/24C07K2317/73C07K2319/00
Inventor GOLDSTEIN, NEIL I.GIORGIO, NICHOLAS A.JONES, STEVEN TARRANSALDANHA, JOSE WILLIAM
Owner GOLDSTEIN NEIL I
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