Potent conjugates and hydrophilic linkers

A technology of conjugates and compounds, applied in the field of hydrophilic linkers and preparation of maytansinoids, which can solve the problems of low yield of final conjugates, heterogeneity of conjugates, expensive and other problems

Inactive Publication Date: 2012-07-18
IMMUNOGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The multiple reaction and purification steps result in low yields of the final conjugate and can be expensive and cumbersome when considering implementing these steps on a large scale
An additional disadvantage of these methods is the conjugate heterogeneity introduced when unreacted cross-linker remains attached to the drug-unattached cell-binding agent

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0371] Without being bound by any particular aspect, polyethylene glycol ((CH) with different reactive linkers for conjugation with cell binding agents is described. 2 CH 2 O) n ) Synthetic method of the drug linked. These conjugation methods include via polyethylene glycol ((CH 2 CH 2 O) n ) one-step conjugation of a linker-linked antibody to a drug such as maytansinoid.

[0372] Furthermore, the synthesis of disulfide-containing polyethylene glycol ((CH 2 CH 2 θ) n ) method of linking the drug. These conjugation methods include the use of polyethylene glycol ((CH 2 CH 2 O) n ) one-step conjugation of the disulfide-linked antibody of the linker to a drug such as maytansinoid.

[0373] The following examples are illustrative only and are not intended to limit the invention.

Embodiment I

[0375] Antibodies with each anti- The body molecule is conjugated to several maytansinoid molecules:

[0376] In a two-step method of conjugating antibodies to several maytansinoid DM4 or DM1 molecules, a commercially available amine-reactive N-hydroxysuccinimide group (NHS group) and A heterobifunctional linker (SPDB) of a reactive 2-pyridyldithio group (-SSPy group) modifies the humanized antibody to incorporate several linker molecules into the antibody molecule (e.g. W.C. Widdison et al., J Med. Chem., 2006, 49, 4392-4408). After incorporation of the reactive linker into the antibody molecule, in a second reaction step, the maytansinoid DM4 or DM1, which has a reactive thiol group, is added to the linker-modified antibody to disulfide bond the maytansinoid Alkaloids are conjugated to antibodies. In a particular example, a 10-15 fold molar excess of commercially available methionine with -(CH 2 )- nAlkyl heterobifunctional linkers (such as SPDB, SPP, SPDP) modify th...

Embodiment II

[0378] By containing a hydrophilic polyethylene oxide spacer (PEG n or (-CH 2 -CH 2 -O) n＝1-14 ) The disulfide linker makes the antibody linked to several maytansinoid molecules per antibody molecule Then conjugate:

[0379] In order to study hydrophilic spacers such as polyethylene oxide (PEG n or (-CH 2 -CH 2 -O) n＝1-14 )) Whether it is possible to prevent the aggregation and precipitation of antibody maytansinoid conjugates with a large number of maytansinoid molecules (on average >4 per antibody molecule), several new heterobifunctional and monofunctional maytansinoid derivatives, which can be conjugated to antibodies by direct modification or a two-step reaction involving initial derivatization of antibodies at lysine residues followed by maytansinoid Alkaloid reactions (see, e.g. image 3 , 6, 11 and 12).

[0380] Synthesis of 15-(2-pyridyldithio)-4,7,10,13-tetraoxapentadecanoic acid

[0381] A solution of 2,2'-dipyridyldisulfide (aldri...

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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 application is a continuation-in-part of US Formal Application No. 12 / 433,668, filed April 30, 2009, which claims priority to US Provisional Application No. 61 / 049,289, filed April 30, 2008. The entire disclosures of the prior applications (Application Nos. 12 / 433,668 and 61 / 049,289) are considered part of the disclosure of the appended continuation applications and are hereby incorporated by reference. field of invention [0002] The present invention relates to novel linkers that link a drug (eg, a cytotoxic agent) to a cell-binding agent (eg, an antibody) in such a way that the linker contributes to increasing the activity of the drug. In particular, the present invention relates to the use of novel hydrophilic linkers, wherein such linkers increase the potency or potency of cell-binding agent-drug conjugates several-fold in various cancer cell types that Cell types include cancer cells that express low numbers of antigens on the cell surface or cancers that are...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D267/22
CPCA61K47/48407A61K47/48569A61K47/48215C07D267/22A61K47/48715C07D498/18A61K47/6889A61K47/60A61K47/6803A61K47/6851A61P31/12A61P33/00A61P35/00A61P35/02A61P37/02A61P37/06A61K31/535
Inventor R·辛S·D·威尔豪姆R·V·J·查理
Owner IMMUNOGEN INC
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