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Anti-cancer anthracycline drug-antibody conjugates

An anthracycline and conjugate technology, applied in the field of therapeutic conjugates, can solve problems such as damage, toxicity, large non-target tissue, etc.

Inactive Publication Date: 2006-04-26
IMMUNOMEDICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, radionuclide mAb conjugates can often be highly toxic due to the presence of circulating decaying radioactivity in large excess compared to tumor-localized activity
Toxin-mAb conjugates have a double disadvantage: large non-target tissue damage and large immunoreactivity to commonly used plant or bacterial proteins
Hydrazone bonds are apparently stable under in vivo serum conditions, disulfide bonds were found to be generally not stable enough for practical use

Method used

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  • Anti-cancer anthracycline drug-antibody conjugates
  • Anti-cancer anthracycline drug-antibody conjugates
  • Anti-cancer anthracycline drug-antibody conjugates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Embodiment 1: the synthesis of 2-PDOX

[0094] Synthesis of 2-pyrrolinyl-doxorubicin (2-PDOX): 4-iodobutyraldehyde: 2-(3-chloropropyl)-1,3-di-oxolane (1.3 mL; 10 mM) dissolved in 200 mL of acetone containing 30 g of sodium iodide (200 mmol; 20-fold excess). The solution was refluxed for 24 hours and evaporated to dryness. The crude mixture was used in the following reactions. Doxorubicin hydrochloride (550 mg, 946 μmol) was dissolved in 6.5 ml of DMF, and 3.86 g (19.48 mmol, 20-fold excess) of 4-iodobutyraldehyde was added, followed by 500 μl of N , N-diisopropylethylamine (DIPEA). After five minutes, the material was purified by reverse phase HPLC on a Waters NovaPak C-18 column with gradient elution. The gradient was: 90:10 eluent A to 70:30 eluent B, 75 ml per minute, over 40 minutes, where eluent A was 0.1% trifluoroacetic acid (TFA) and eluent B contained 0.1 % TFA in 90% acetonitrile. Electron spray mass spectrometry confirmed the identity of the product, M+...

Embodiment 2

[0095] Example 2: Conjugation of 2-PDOX to anti-CD22 antibody humanized LL2 (hLL2)

[0096] a) Activation of 2-PDOX: 2-PDOX (5.95 mg; 1×10 -5 mol) with one molar equivalent of the commercially available linker 4-(N-maleimidomethyl)cyclohexane-1-carboxyhydrazide (M 2 C 2 H; Pierce Chemical Co., Rockford, IL) (2.88 mg; 1 x 10 -5 mol) in 0.5 mL of dimethyl sulfoxide (DMSO). The reaction mixture was heated at 50-60°C for 30 minutes under reduced pressure. The desired product was purified by preparative RP-HPLC using a gradient consisting of 0.3% ammonium acetate and 90% acetonitrile, 0.3% ammonium acetate in pH 4.4, eluting from mostly unreacted 2-PDOX (early about 0.5 min) and separation of the desired product from unreacted M2C2H (eluting earlier). The amount recovered was estimated by reference to the UV absorbance level of the sample (496 nm) relative to a standard solution of 2-PDOX in acetonitrile / ammonium acetate buffer. If not used immediately, maleimide-activated 2-...

Embodiment 3

[0099] Example 3: Conjugation of 2-PDOX to anti-CD74 antibody humanized LL1 (hLL1)

[0100] a) Activation of 2-PDOX: 2-PDOX (5.95 mg; 1×10 -5 mol) with one molar equivalent of the commercially available linker 4-(N-maleimidomethyl)cyclohexane-1-carboxyhydrazide (M2C2H; Pierce Chemical Co., Rockford, IL) ( 2.88 mg; 1 x 10 -5 mol) in 0.5 mL DMSO. The reaction mixture was heated at 50-60°C for 30 minutes under reduced pressure. The desired product was purified by preparative RP-HPLC using a gradient consisting of 0.3% ammonium acetate and 90% acetonitrile, 0.3% ammonium acetate in pH 4.4, eluting from mostly unreacted 2-PDOX (early about 0.5 min) and separation of the desired product from unreacted M2C2H (eluting earlier). The amount recovered was estimated by reference to the UV absorbance level of the sample (496 nm) relative to a standard solution of 2-PDOX in acetonitrile / ammonium acetate buffer. If not used immediately, maleimide-activated 2-PDOX was frozen and lyophili...

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Abstract

The present invention relates to therapeutic conjugates with the ability to target various antigens. The conjugate contains a targeting antibody or an antigen-binding fragment thereof and an anthracycline chemotherapy drug. The targeting antibody and the anthracycline chemotherapy drug are linked via a linker that includes a hydrazide moiety.

Description

field of invention [0001] The present invention relates to therapeutic conjugates with the ability to target various antigens. The conjugate comprises a targeting moiety and a chemotherapeutic drug. The targeting moiety and the chemotherapeutic drug are linked by a linker containing an intracellular cleavable moiety. Background of the invention [0002] Antibodies that can be used to specifically deliver chemotherapy drugs to human cancers have been a goal of scientists in the field of specificity-directed drug therapy for many years. Achieving this goal could eventually bring the concept of a magic bullet to cancer chemotherapy. Significant progress toward this goal came with the advent of the hybridoma technology of Kohler and Milstein in 1975, and the ensuing ability to produce monoclonal antibodies (mAbs). Over the past 25 years, mAbs have been prepared against many antigenic targets overexpressed on cancer cells. A number of mAbs have been tested preclinically and s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K39/395C07K16/46
CPCA61K47/6889A61K47/6809A61K47/6849A61P35/00A61P35/02A61P37/02A61P37/04A61P43/00A61K47/50A61K39/395
Inventor G·L·格里菲思斯
Owner IMMUNOMEDICS INC
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