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

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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