46 results about "Maitansine" patented technology

New thiol and disulfide-containing maytansinoids bearing a mono or di-alkyl substitution on the α-carbon atom bearing the sulfur atom are disclosed. Also disclosed are methods for the synthesis of these new maytansinoids and methods for the linkage of these new maytansinoids to cell-binding agents. The maytansinoid-cell-binding agent conjugates are useful as therapeutic agents, which are delivered specifically to target cells and are cytotoxic. These conjugates display vastly improved therapeutic efficacy in animal tumor models compared to the previously described agents.

The invention provides a one-step process for preparing a cell-binding agent cytotoxic agent conjugate comprising contacting a cell-binding agent with a cytotoxic agent to form a first mixture comprising the cell-binding agent and the cytotoxic agent and contacting the first mixture comprising the cell-binding agent and the cytotoxic agent with a bifunctional crosslinking reagent, which provides a linker, in a solution having a pH of about 4 to about 9 to provide a second mixture comprising the cell-binding agent cytotoxic agent conjugate, wherein the cell-binding agent is chemically coupled through the linker to the cytotoxic agent, free cytotoxic agent, and reaction by-products. The second mixture is then optionally subjected to purification to provide a purified cell-binding agent cytotoxic agent conjugate.

Methods and compositions for the development of effective cancer therapies using mitotic inhibitors which have limited general toxicity to normal, non-cancerous cells and tissues are provided. The methods and compositions utilize cytotoxic compounds comprised of a cell-binding agent (e.g., antibodies) conjugated to an anti-mitotic compound (e.g., maytansinoids). The invention further provides antibodies which are substantially incapable of inducing antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC), thereby ensuring that the therapeutic effect is mediated primarily by the anti-mitotic component of the cytotoxic compound, rather than by indirect cell killing via ADCC and/or CDC. The antibodies of the invention further are capable of differentiating between polypeptide antigens which are more highly expressed on proliferating cancer cells as compared to proliferating non-cancer cells.

New thiol and disulfide-containing maytansinoids bearing a mono or di-alkyl substitution on the alpha-carbon atom bearing the sulfur atom are disclosed. Also disclosed are methods for the synthesis of these new maytansinoids and methods for the linkage of these new maytansinoids to cell-binding agents. The maytansinoid-cell-binding agent conjugates are useful as therapeutic agents, which are delivered specifically to target cells and are cytotoxic. These conjugates display vastly improved therapeutic efficacy in animal tumor models compared to the previously described agents.

A microorganism that is a mutant bacterial strain of the species Actinosynnema pretiosum, designated PF4-4, (ATCC PTA-3921), being capable of producing maytansinoid ansamitocins such as ansamitocin P-3 in improved yield compared to previous known strains, and capable of growth under varied culture conditions, and methods of producing maytansinoid ansamitocins by culturing PF4-4 in a suitable growth medium.

The application concerns methods of treatment using anti-ErbB receptor antibody-maytansinoid conjugates, and articles of manufacture suitable for use in such methods. In particular, the invention concerns ErbB receptor-directed cancer therapies, using anti-ErbB receptor antibody-maytansinoid conjugates.

The invention provides a liquid composition and a lyophilized composition comprising a therapeutically effective amount of a conjugate comprising an antibody chemically coupled to a maytansinoid. The invention further provides a method for killing a cell in a human comprising administering to the human either of the compositions such that the antibody binds to the surface of the cell and the cytotoxicity of the maytansinoid is activated, whereby the cell is killed.

The invention provides process for preparing antibody-drug conjugates, preferably trastuzumab maytansinoid conjugate linked via non-cleavable linker comprising performing the conjugation reaction at lower temperature than ambient and/or at lower pH condition than neutrality. The process according to the present invention comprises conjugating the linker modified antibody with cytotoxic drug, preferably the SMCC-modified trastuzumab with a cytotoxic drug, preferably maytansinoid at a temperature lower than 20° C. and at a pH lower than 6.0, and thereby preparing an antibody-drug conjugate, preferably trastuzumab maytansinoid conjugate, T-DM1.

The invention provides polypeptide prodrug, which is prodrug formed by monomethyl dolastatin medicine or Maitansine and Evans blue. A structure formula of the polypeptide prodrug is shown as a formula(I), wherein R1 is one kind of materials from a material shown in the description or -CH2-; R2 is one kind of materials from polypeptide medicine of monomethyl dolastatin or Maitansine structures; mand n are repeated unit number and are integers being 0 to 4. The polypeptide medicine prodrug has the excellent tumor cell taking effects in vivo and in vitro; a part of prodrug also shows the obvious cancer cell inhibition effects. The invention also provides a preparation method of the prodrug and application of the prodrug in the cancer treatment medicine. (The formula is shown in the description.).

The present invention provides immunoconjugates composed of antibodies, e.g., monoclonal antibodies, or antibody fragments that bind to mesothelin, that are conjugated to cytotoxic agents, e.g., maytansine, or derivatives thereof, and/or co-administered or formulated with one or more additional anti-cancer agents. The immunoconjugates of the invention can be used in the methods of the invention to treat and/or diagnose and/or monitor cancers, solid tumors, recombinant antigen-binding regions and antibodies and functional fragments containing such antigen-binding regions that are specific for the membrane-anchored, 40 kDa mesothelin polypeptide, which which is overexpressed in several tumors, such as pancreatic and ovarian tumors, mesothelioma and lung cancer cells.

Disclosed herein are maytansinoid drug linker derivatives which can be linked to a antigen binding unit (Abu), and maytansinoid drugs linked with an antigen binding unit (Drug-Linker-Antigen binding Unit: D-L-Abu), for targeted delivery to disease tissues. D-L-Abu, D-L-Abu derivatives, and methods relating to the use of such drug conjugates to treat antigen positive cells in cancers and immunological disorders are provided.

The present disclosure provides anti-CD22 antibody-maytansine conjugate structures. The disclosure also encompasses methods of production of such conjugates, as well as methods of using the same.

The invention discloses a process for the preparation of maytansinoid esters of formula (I) comprising a thiol or disulphide group wherein R¹, R⁴ and R⁵ and the asterisk are as defined in the description, by reacting maytansinol with an enantiopure alpha-azido acid, followed by reduction of the azido group and reacting the obtained amino-ester with a compound of formula (IX) (IX) R³—S—S—X—COOH wherein X and R³ are as defined in the description, or with a reactive derivative thereof and optionally reducing the obtained disulfide-containing maytansinoid ester to give a maytansinoid ester wherein R¹ is a —X—SH group.

The invention relates to a maytansine polypeptide conjugate as well as a preparation method and application thereof. The conjugate has a molecular structure of a formula I shown in the description; inthe formula, Aaa1 is L or D-type Lys or Arg; Aaa2 is any L or D-type natural amino acid; Aaa3 is any L or D-type natural amino acid; Aaa4 is L or D-type Lys or Arg; R1 is cyclohexyl or -(CH2)n-; n is1-10; and R2-SH is maytansine DM1 or DM4. The maytansine polypeptide conjugate provided by the invention is capable of achieving targeted drug administration, meanwhile, a (Cend R)-R/KXXR/K (R: arginine, K: lysine, and X: any amino acid) sequence which meets rules of a C end is introduced to the C end to improve the transmembrane capability of the medicine to tumor cells, then the medicine can rapidly enter cells, the treatment effect of the medicine can be improved, and toxic and side effects on normal cells can be alleviated.