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Potent conjugates and hydrophilic linkers

a technology of conjugates and hydrophilic links, applied in the field of new linkers, can solve the problems of low to modest anti-tumor activity in patients, loss of biological activity, and diminished potency of drugs, and achieve the effect of improving the manner in which drugs are linked and increasing the activity of drugs

Inactive Publication Date: 2012-09-06
IMMUNOGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The PEG-linked conjugates exhibit significantly enhanced cytotoxicity, particularly against multidrug-resistant cancer cells, with a 260-650 fold potency increase and improved stability and monomer percentage, overcoming the limitations of traditional linkers in terms of yield and aggregation.

Problems solved by technology

Although, antibody-cytotoxic drug conjugates show cell killing activity in vitro and anti-tumor activity in vivo, their potency is diminished in many cases, especially when the antigen expression on the target cancer cell is low, or when the target cells are resistant to the treatment.
This is often the case in the clinical setting, resulting in low to modest anti-tumor activity in patients.
However, this process is cumbersome and several analogs have to be synthesized, and often modification in the structure of the drug results in loss of biological activity.
These multiple reaction and purification steps result in low yield of the final conjugate and can be expensive and cumbersome when one considers implementing these steps on a large scale.
An additional drawback to these methods is the conjugate heterogeneity that is introduced when unreacted crosslinker remains linked to the cell-binding agent without attached drug.

Method used

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  • Potent conjugates and hydrophilic linkers
  • Potent conjugates and hydrophilic linkers
  • Potent conjugates and hydrophilic linkers

Examples

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examples

[0211]Without being bound by any particular aspect, methods are described for the synthesis of polyethylene glycol ((CH2CH2O)n)-linked drugs with different reactive linkers for conjugation with cell-binding agents. These conjugation methods include a one-step conjugation of antibody with drugs such as maytansinoids linked via polyethylene glycol ((CH2CH2O)n) linker by reaction at N-hydroxysuccinimide (NHS) reactive group.

[0212]Also, described are methods of synthesizing disulfide-group containing polyethylene glycol ((CH2CH2O)n)-linked drugs with different reactive linkers for conjugation with antibody. These conjugation methods include a one-step conjugation of antibody with drugs such as maytansinoid linked with disulfide-group having polyethylene glycol ((CH2CH2O)n) linker via reaction at a N-hydroxysuccinimide (NHS) reactive group.

[0213]The following examples, which are illustrative only, are not intended to limit the present invention.

example i

Conjugation of Antibody with Several Maytansinoid Molecules Linked Per Antibody Molecule by Disulfide Linkers Containing Traditional Aliphatic Carbon Spacers

[0214]In a two-step process to conjugate an antibody with several molecules of the maytansinoid DM4 or DM1, a humanized antibody was first modified with a commercially available heterobifunctional linker (SPDB) containing both an amine-reactive N-hydroxysuccinimide group (NHS group) and a thiol-reactive 2-pyridyldithio group (-SSPy group) to incorporate several molecules of the linker in the antibody molecule (as described in W. C. Widdison et al., J. Med. Chem., 2006, 49, 4392-4408). Following the incorporation of the reactive linkers in the antibody molecule, in a second reaction step the maytansinoid DM4 or DM1 with a reactive thiol group was added to the linker-modified antibody to conjugate the maytansinoid to antibody by disulfide bonds. In a specific example, a humanized antibody at a concentration of 5-10 mg / ml was modif...

example ii

Conjugation of Antibody with Several Maytansinoid Molecules Linked Per Antibody Molecule by Disulfide Linkers Containing Hydrophilic Polyethylene Oxide Spacers (PEGn, or (—CH2—CH2—O)n=1-14)

[0215]To explore if hydrophilic spacers such as polyethylene oxide (PEGn, or (—CH2—CH2—O)n=1-14) could perhaps prevent the aggregation and precipitation of antibody-maytansinoid conjugates with a high number of maytansinoid molecules (>4 average per antibody molecule), several new heterobifunctional and monofunctional maytansinoid derivatives were prepared which could be conjugated to antibody by direct modification or a two-step reaction involving the initial derivatization of antibody at lysine residues followed by the reaction of maytansinoids (see, for examples, FIGS. 3, 6, 11, and 12).

Synthesis of 15-(2-pyridyldithio)-4,7,10,13-tetraoxapentadecanoic acid

[0216]A solution of aldrithiol-2 (1.17 g, 5.31 mmol) was prepared in 5.0 mL of 1,2-dimethoxyethane in a 10 mL round bottom flask. To the reac...

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Abstract

Linkers for binding drugs to cell binding agents are modified to hydrophilic linkers by incorporating a polyethylene glycol spacer. The potency or the efficacy of the cell-binding agent-drug conjugates is surprisingly enhanced several folds in a variety of cancer cell types, including those expressing a low number of antigens on the cell surface or cancer cells that are resistant to treatment. A method for preparing maytansinoids bearing a thioether moiety and a reactive group which allows the maytansinoid to be linked to a cell-binding agent in essentially a single step is also provided.

Description

[0001]This is a continuation of U.S. application Ser. No. 12 / 574,466 filed Oct. 6, 2009.FIELD OF THE INVENTION[0002]The present invention relates to new linkers to link drugs (e.g. cytotoxic agents) to cell-binding agents (e.g., antibodies) in such a way that the linker contributes in increasing the activity of the drug. In particular, the present invention relates to the use of novel hydrophilic linkers, wherein such linkers enhance the potency or the efficacy of the cell-binding agent-drug conjugates by several fold in a variety of cancer cell types, including those expressing a low number of antigens on the cell surface or cancers that are resistant to treatment. The present invention also relates to a method for preparing maytansinoids bearing a thioether moiety and a reactive group which allows the maytansinoid to be linked to a cell-binding agent.BACKGROUND OF THE INVENTION[0003]Antibody conjugates of cytotoxic drugs are being developed as target-specific therapeutic agents. A...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K1/113C07D498/18
CPCA61K47/48384A61K47/48569A61K47/48715C07K2317/24C07K16/2803C07K16/30C07D498/18A61K47/6889A61K47/60A61K47/54A61K47/6843A61K47/6849A61K47/6851A61K47/6863A61K47/6891A61K31/5386A61P31/12A61P33/00A61P35/00A61P37/00A61P37/02A61P37/06Y02A50/30A61K47/68033A61K31/40A61K31/537A61K39/395A61K47/6803
Inventor SINGH, RAJEEVAWILHELM, SHARON D.CHARI, RAVI V.J.
Owner IMMUNOGEN INC
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