Novel Class of Monospecific and Bispecific Humanized Antibodies that Target the Insulin-like Growth Factor Type I Receptor (IGF-1R)

a technology of insulinlike growth factor and humanized antibodies, which is applied in the field of monospecific and bispecific humanized antibodies that target the insulinlike growth factor type i receptor (igf1r), can solve the problems of limited use of such agents in cancer therapy

Inactive Publication Date: 2010-09-09
IMMUNOMEDICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]The present invention provides compositions and methods of use of anti-IGF-1R antibodies or antigen-binding fragments thereof. In preferred embodiments, the anti-IGF-1R antibodies bind to IGF-1R but not to IR. In more preferred embodiments the anti-IGF-1R antibodies are not agonists of IGF-1R. In most preferred embodiments, the anti-IGF-1R antibodies bind to an epitope of IGF-1R comprising the first half of the cysteine-rich domain of IGF-1R, between amino acid residues 151 and 222 of the human IGF-1R sequence. (See, e.g., Adams et al., Cell Mol Life Sci 57:1050-93, 2000; NCBI Accession No. AAB22215). Protease cleavage by furin results in production of the α- chain, comprising residues 1-706, and the 13-chain, comprising residues 711-1337. Residues 151-222 consists of the N-terminal half of the cysteine-rich domain (residues 151-300).

Problems solved by technology

The use of such agents for cancer therapy has been limited by their toxicity (Riedemann and Macaulay, 2006).

Method used

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  • Novel Class of Monospecific and Bispecific Humanized Antibodies that Target the Insulin-like Growth Factor Type I Receptor (IGF-1R)
  • Novel Class of Monospecific and Bispecific Humanized Antibodies that Target the Insulin-like Growth Factor Type I Receptor (IGF-1R)
  • Novel Class of Monospecific and Bispecific Humanized Antibodies that Target the Insulin-like Growth Factor Type I Receptor (IGF-1R)

Examples

Experimental program
Comparison scheme
Effect test

example 1

Generation and Initial Characterization of Anti-IGF-1R Antibodies: R1, cR1, and hR1

[0173]Three BALB / c mice were each immunized i.p. with 15 μg of recombinant human IGF-1R (R&D Systems, Catalog #391-GR), comprising a mixture of both processed and unprocessed extracellular domain of human IGF-1R, in complete Freund's adjuvant. Additional immunizations in incomplete Freund's adjuvant were done 14, 21, and 28 days after the initial immunization. Spleen cells from the immunized mice were fused with P3X63Ag8.653 cells to generate hybridomas according to standard protocols. One clone (C-11) expressing anti-IGF-1R but not anti-IR (insulin receptor) activity was isolated and expanded in cultures to obtain the mouse antibody designated ML04R1 or R1, which was shown to be an IgG1 / k with the ability to inhibit the binding of radioiodinated IGF-1 to the IGF-1R expressing human breast cancer cell line MCF-7L (a subline of MCF-7) comparable to a commercially available mouse anti-IGF-1R monoclonal ...

example 2

Epitope Mapping Studies of R1, cR1, and hR1

[0178]To further locate the region of IGF-1R to which hR1 binds, a panel of commercially available anti-IGF-1R mAbs that have their epitopes to IGF-1R mapped, were evaluated for their ability to cross-block each other from binding to the IGF-1R-coated beads. The results of two typical experiments are provided in FIG. 8A, which shows the binding of R1 tagged with a fluorescent probe (PE) was not affected by MAB391 even at 100 μg / mL, and FIG. 8B, which shows the binding of MAB391 tagged with PE was only partially inhibited (50 to 60%) by R1 at 100 μg / mL. Additional results summarized in Table 3A indicate that the epitope of R1 is located in the CR domain between aa 151 and 282 and can be further located to the first half of the CR domain between aa 151 and 222 (Table 3B).

TABLE 3A% binding of each labeled antibody (*) to rhIGF-1R-coated beads in the presenceof the unlabeled antibody (24-31, 24-57, 17-69, 1-2, 1H7, 2C8, 3B7)Anti-IGF-1R24-3124-5...

example 3

Additional Characterization of R1, cR1, and hR1

[0179]Whereas IGF-1 stimulates proliferation of MCF-7 cells grown in serum-free medium, achieving a maximal effect of 50% increase in viable cell counts at 100 ng / mL when compared to the untreated control at 48 h, hR1 does not (FIG. 9). Thus hR1 is not agonistic upon binding to IGF-1R. Internalization of hR1 into MCF-7 was observed at 37° C. but not at 4° C. (not shown).

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Abstract

The present invention provides compositions and methods of use of anti-IGF-1R antibodies or antibody fragments. Preferably the antibodies bind to IGF-1R but not IR; are not agonists for IGF-1R; do not block binding of IGF-1 or IGF-2 to isolated IGF-1R, but effectively neutralize activation of IGF-1R by IGF-1 in intact cells; and block binding of an R1 antibody to IGF-1R. The antibodies may be murine, chimeric, humanized or human R1 antibodies comprising the heavy chain CDR sequences DYYMY (SEQ ID NO:1), YITNYGGSTYYPDTVKG (SEQ ID NO:2) and QSNYDYDGWFAY (SEQ ID NO:3) and the light chain CDR sequences KASQEVGTAVA (SEQ ID NO:4), WASTRHT (SEQ ID NO:5) and QQYSNYPLT (SEQ ID NO:6). Preferably the antibodies bind to an epitope of IGF-1R comprising the first half of the cysteine-rich domain of IGF-1R (residues 151-222). The anti-IGF-1R antibodies may be used for diagnosis or therapy of various diseases such as cancer.

Description

FIELD OF THE INVENTION[0001]The present application is a continuation-in-part of U.S. patent application Ser. No. 12 / 689,336, filed Jan. 19, 2010, which claimed the benefit under 35 U.S.C. 119(e) of Provisional U.S. Patent Application Ser. No. 61 / 145,896, filed Jan. 20, 2009, each priority application incorporated herein by reference in its entirety.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Mar. 9, 2010, is named IMM31US2.txt, and is 19,199 bytes in size.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The present invention relates to antibodies and antigen-binding antibody fragments that bind to the insulin-like growth factor type I receptor (IGF-1R), but not to the insulin receptor (IR). In preferred embodiments, the anti-IGF-1R antibody is not an agonist for IGF-1R. In more preferred embodiments, the anti-IGF-1R a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/21C07K16/22C12P21/08G01N33/53A61K39/395A61K38/20C07H21/04C12N15/63C12N5/00C12P21/04
CPCA61K31/7068A61K51/1057A61K47/48561A61K51/103C07K16/2863C07K2317/24C07K2317/31C07K2317/53C07K2317/55C07K2317/565C07K2319/735G01N33/57484A61K39/39558A61K45/06C07K2317/52A61K2300/00A61K31/69A61K47/6849A61P35/00A61K47/6851C07H21/04A61K39/3955A61K47/6803A61K47/6811A61K47/6845A61K47/6847A61K51/1063A61K51/1093A61K2039/505C07K14/475C07K14/705C07K16/28C07K16/30C07K16/3015C07K16/303C07K16/3046C07K16/3069C07K2317/33C07K2317/34C07K2317/522C07K2317/56C07K2317/64C07K2317/76C07K2319/74C12N15/11
Inventor CHANG, CHIEN-HSINGLOSMAN, MICHELE J.GOLDENBERG, DAVID M.
Owner IMMUNOMEDICS INC
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