Anti-IGF-I receptor antibody

An antibody and receptor technology, applied in the direction of antibodies, antibody medical components, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc.

Inactive Publication Date: 2006-12-27
IMMUNOGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] [17] Due to the weak agonistic activity of IR3 and other reported antibodies, and their inability to significantly inhibit the growth of tumor cells such as MCF-7 cells under more physiological conditions such as serum stimulation (the serum stimulation described here is different from that in the absence of stimulatory effect of exogenously added IGF-I or IGF-II under serum conditions), so there is a need for new anti-IGF-I that can significantly inhibit the serum-stimulated growth of tumor cells, but does not itself show significant agonist activity receptor antibody

Method used

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Examples

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Embodiment 1

[0119] Example 1: Mouse EM164 Antibody

[0120] [105] In this first example, the complete primary amino acid structure and cDNA sequence of the murine antibody of the present invention are disclosed, as well as its binding properties and the manner in which it is expressed in recombinant form. Accordingly, the antibodies of the present invention and their preparation are fully and completely disclosed such that a person of ordinary skill in the field of immunology will be able to prepare the same without undue experimentation.

[0121] A. Generation of Anti-IGF-1 Receptor Monoclonal Antibody Hybridomas

[0122] [106] used a cell line expressing the human IGF-I receptor with the Y1251F mutation for immunization because it expresses a large number of IGF-I receptors (~10 7 / cell). The Y1251F mutation in the cytoplasmic domain of the IGF-I receptor results in loss of transforming and anti-apoptotic signaling functions, but does not affect IGF-I binding and IGF-I-stimulated mito...

Embodiment 2

[0194] Example 2: Humanized version of EM164 antibody

[0195] [160] Resurfacing of the EM164 antibody was performed generally according to the principles and methods disclosed in US Patent No. 5,639,641 and as follows to provide a humanized form of the antibody suitable as a therapeutic or diagnostic reagent.

[0196] A. Surface Prediction

[0197] [161] To predict the surface residues of the variable region of a murine anti-IGF-I receptor antibody (EM164), the solvent accessibility of variable region residues of a set of antibodies with dissolved structures was used. The MC software package was used to calculate the solvent solubility of amino acids for a set of 127 unique antibody structure files (Table 2) (Pedersen et al., 1994, J. Mol. Biol., 235, 959-973). Through sequence alignment, 10 most similar amino acid sequences of light chain and heavy chain were determined from these 127 structures. The average solvent accessibility was calculated for each variable region res...

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Abstract

Antibodies, humanized antibodies, resurfaced antibodies antibody fragments, derivatized antibodies, and conjugates of same with cytotoxic agents, which specifically bind to, and inhibit, insulin-like growth factor-I receptor, antagonize the effects of IGF-I, IGF-II and serum on the growth and survival of tumor cells, and which are substantially devoid of agonist activity. The antibodies and fragments thereof may be used, optionally in conjunction with other therapeutic agents, in the treatment of tumors that express elevated levels of IGF-I receptor, such as breast cancer, colon cancer, lung cancer, ovarian carcinoma, synovial sarcoma, prostate cancer and pancreatic cancer and the derivatized antibodies may be used in the diagnosis and imaging of tumors that express elevated levels of IGF-I receptor.

Description

[0001] [01] This application is a continuation-in-part of parent application 10 / 170,390, filed June 14, 2002, which parent application is hereby incorporated by reference in its entirety. field of invention [0002] [02] The present invention relates to antibodies that bind to human insulin-like growth factor-I receptor (IGF-I receptor). More specifically, the present invention relates to anti-IGF-I receptor antibodies that inhibit the cellular function of IGF-I receptor. More specifically, the invention relates to antibodies that antagonize the effects of IGF-I, IGF-II, and serum on tumor cell growth and survival, which substantially lack agonist activity. The present invention also relates to fragments of said antibodies, humanized and resurfaced forms of said antibodies, conjugates of said antibodies, derivatives of said antibodies, and their Uses in diagnostic, research and therapeutic applications. The present invention further relates to improved antibodies or fragment...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/00A61K39/395C07H21/04C12N15/00
CPCC07K16/2863C07K2317/565A61K39/39541A61K2039/505C07K2317/55C07K2317/56C07K2316/96C07K2317/24C07K2317/76A61K2300/00C07K16/28C07K16/18
Inventor R·辛格D·J·塔瓦雷斯N·E·达地吉恩
Owner IMMUNOGEN INC
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