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Novel class of monospecific and bispecific humanized antibodies that target the insulin-like growth factor type i receptor (IGF-1R)

One-IGF-1R, IGF-1R technology, applied in the field of new monospecific and bispecific humanized antibodies targeting insulin-like growth factor type I receptor (IGF-1R), can solve toxicity, Restrictions and other issues

Active Publication Date: 2012-10-10
IMMUNOMEDICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of such agents for cancer therapy has been limited due to 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

Embodiment 1

[0217] Example 1. Generation and preliminary characterization of anti-IGF-1R antibodies: R1, cR1 and hR1

[0218] Each of 3 BALB / c mice was immunized intraperitoneally with 15 μg of recombinant human IGF-1R (R&D Systems, Catalog #391-GR) containing human IGF-1R in complete Freund's adjuvant. Processed and unprocessed extracellular domains of 1R. Additional immunizations in incomplete Freund's adjuvant were performed on days 14, 21 and 28 after the primary immunization. Splenocytes from immunized mice were fused with P3X63Ag8.653 cells according to standard protocols to generate hybridomas. One clone (C-11) expressing anti-IGF-1R but not anti-IR (insulin receptor) activity was isolated and expanded in culture to obtain a mouse antibody called ML04R1 or R1, which IgG1 / kappa shown to have the ability to inhibit the binding of radioiodinated IGF-1 to the IGF-1R expressing human breast cancer cell line MCF-7L (subline of MCF-7), which can be compared with commercially available ...

Embodiment 2

[0231] Example 2. Epitope mapping studies of R1, cR1 and hR1

[0232] To further map the region of IGF-1R where hR1 binds, a panel of commercially available anti-IGF-1R mAbs that had mapped their epitopes against IGF-1R were evaluated for their cross-blocking with IGF-1R coating the binding capacity of the beads. Figure 8 The results of two typical experiments are provided in A showing that the binding of R1 labeled with a fluorescent probe (PE) is not affected by even 100 μg / mL of MAB391, Figure 8 B shows that binding with PE-labeled MAB391 is only partially inhibited (50 to 60%) by 100 μg / mL of R1. 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 localized in the first half of the CR domain between aa 151 and 222 (Table 3B).

[0233] Table 3A Each labeled antibody (*) with rhIGF-1R-coated beads in the presence of unlabeled antibodies (24-31, 24-57, 17-69, 1-2, 1H7, 2C8, 3B7) %...

Embodiment 3

[0237] Example 3. Additional characterization of R1, cR1 and hR1

[0238] While IGF-1 stimulated the proliferation of MCF-7 cells grown in serum-free medium, resulting in a maximal effect of a 50% increase in viable cell counts at 100 ng / mL when compared to untreated controls at 48 hours, hR1 does not have this effect ( Figure 9 ). Thus hR1 does not antagonize the 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 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; effectively neutralize activation of IGF-1R by IGF-1 in intact cells; block binding of R1 antibody to IGF-1R. The antibodies may be murine, chimeric, humanized or human R1 antibodies comprising heavy chain CDR sequences DYYMY (SEQ ID NO:1), YITNYGGSTYYPDTVKG (SEQ ID NO:2) and QSNYDYDGWFAY (seq id no:3) and light chain CDR sequences KASQEVGTAVA (seq id no:4), WASTRHT (SEQ ID NO:5) and QQYSNYPLT (SEQ ID NO:6). Preferably the antibodies bind 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 invention [0001] This application claims priority to PCT Patent Application Serial No. PCT / US10 / 21345, filed January 19, 2010, which is incorporated herein by reference in its entirety. [0002] sequence listing [0003] This application includes a Sequence Listing that has been submitted via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on March 9, 2010, is named IMM316WO2.txt and is 19,152 bytes in size. Background of the invention field of 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-IR) but not to the insulin receptor (IR). In preferred embodiments, the anti-IGF-1R antibody is not an agonist of IGF-1R. In a more preferred embodiment, the anti-IGF-1R antibody binds to an epitope of IGF-1R that comprises the first half of the cysteine-rich domain of IGF-1R, at amino acid residues Between 151 and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K51/00C07K16/30C07K16/46
CPCC07K2317/53C07K16/2863C07K2317/35A61K51/1057C07K2317/77A61K39/3955A61K2039/505C07K2317/76A61K51/103C07K2317/55C07K16/30A61P35/00A61P35/02A61P43/00A61K2300/00
Inventor C·H·张M·J·洛斯曼D·M·戈德堡
Owner IMMUNOMEDICS INC
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