646502-53-6

Basic information

• Product Name: VcMMAE
• Synonyms: VcMMAE;MC-Val-Cit-PAB-MMAE;Maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl-monomethyl auristatin E;4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-y;MC-VC-PAB-MMAE,MC-Val-Cit-PAB-MMAE;maleimido-caproyl-val-Cit-PAB-MMAE;VeMMAE;EOS-60990
• CAS NO: 646502-53-6
• Molecular Formula: C68H105N11O15
• Molecular Weight: 1316.626
• Mol File: 646502-53-6.mol

Chemical Properties

• Boiling Point: 1347.6±65.0 °C(Predicted)
• Appearance: /
• Density: 1.196±0.06 g/cm3(Predicted)
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Soluble in DMSO, DCM, DMF
• PKA: 13.29±0.70(Predicted)
• CAS DataBase Reference: VcMMAE(CAS DataBase Reference)
• NIST Chemistry Reference: VcMMAE(646502-53-6)
• EPA Substance Registry System: VcMMAE(646502-53-6)

Safety Data

• Hazardous Substances Data: 646502-53-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
VcMMAE is used as a precursor for antibody drug conjugates for the development of targeted cancer therapies. The MMAE payload, a synthetic antineoplastic agent, can be attached to a monoclonal antibody (MAB) to selectively target and kill cancer cells while minimizing damage to healthy cells.
Used in Tumor-Targeting Applications:
Vedotin, an ultra-high-affinity small organic ligand of fibroblast activation protein, is used in conjunction with VcMMAE for tumor-targeting applications. This combination allows for the specific delivery of the MMAE payload to cancer cells, enhancing the therapeutic efficacy and reducing side effects associated with traditional chemotherapy.

Upstream product

• 55750-63-5 6-maleimidohexanoic acid N-hydroxylsuccinimide ester 
• 159857-81-5 N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N⁵-carbamoyl-N[4-({[(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide 
• 474645-27-7 [3H]-Vedotin 
• 68858-20-8 Fmoc-Val-OH 
• 372-75-8 Citrulline 
• 159858-21-6 (S)-2-((S)-2-((((9H-fluoren-9-yl)-methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid 
• 159858-22-7 (9H-fluorenyl)methyl ((S)-1-(((S)-1-(((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidovalerylamido-2-yl)amino))-3-methylbutyramido-2-yl)-carbamate 
• 159857-79-1 (2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-N-[4-(hydroxymethyl)phenyl]-5-ureidopentanamide 
• 159857-80-4 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide 
• 60-32-2 6-aminohexanoic acid 
• 55750-53-3 2,5-Dihydro-2,5-dioxo-1H-pyrrole-1-hexanoic acid 
• 623-04-1 4-aminobenzenemethanol 
• 130878-68-1 2,5-dioxopyrrolidin-1-yl-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valinate 
• 1375415-93-2 tert-butyl (3R,4S,5S)-4-[(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-N,3-dimethylbutanamido]-3-methoxy-5-methylheptanoate 

Relevant articles and documents

Development of bifunctional anti-PD-L1 antibody MMAE conjugate with cytotoxicity and immunostimulation

In recent years, tumor immunotherapy, especially the combination of PD1/PD-L1 inhibitors and chemotherapy, has developed rapidly. However, the systemic side effects induced by chemotherapy remain a crucial problem that needs to be addressed. Antibody drug conjugates (ADCs) are exceptional target-specific prodrugs that greatly improve the therapeutic window of chemotherapy drugs. Therefore, designing PD-L1-targeting ADCs is an interesting research project. In this study, we confirmed for the first time that the commercial anti-PD-L1 antibody Atezolizumab has better endocytosis efficiencies than Avelumab, and was more suitable for ADC design. Then, the most popular cytotoxic payload MMAE was conjugated to Atezolizumab via a classical dipeptide (valine-alanine) linker to generate a bifunctional PD-L1 ADC (ADC 3). An in vitro cytotoxicity test indicated the potent tumor cell inhibitory activity of ADC 3, with EC50 values of 9.75 nM to 11.94 nM. In addition, a co-culture of PBMCs in vitro proved that ADC 3 retained the immune activation effect of the Atezolizumab antibody. Moreover, ADC 3 exhibited a higher tumor inhibition rate and tumor regression rate in humanized immune system mice. To the best of our knowledge, this is the most active PD-L1-ADC reported thus far, which may promote the development of immunotherapy and novel ADCs.

ONE-POT PROCESS FOR PREPARING INTERMEDIATE OF ANTIBODY-DRUG CONJUGATE

The present invention relates to a “one-pot process” for preparing intermediate of antibody-drug conjugate. The preparation process provided by the present invention is simple in operation, and needs no such steps like concentration, washing and filtratio

EFFICIENT PREPARATION OF DOLASTATIN AND AURISTATIN ANALOGS THROUGH A COMMON INTERMEDIATE

Methods for making a dolastatin, auristatin or related compounds comprising the steps of providing a universal dolastatin core of Formula (I) reacting the C-terminal carboxylic acid group with an amine (A) to form an amide bond and reacting the N-terminal amine with a carboxylic acid (CA) to form an amide bond, wherein the steps can be performed in either order. Also provided are an isolated salt of the universal dolastatin core for use in preparation of dolastatins, auristatins and related compounds. Also provided are a number of intermediates and process steps which are useful for the preparation of high purity dolastatin core and high purity dolastatin and auristatin compounds.

An antibody-coupled drug targeting on EGFR, a preparation method thereof, and uses thereof

The invention discloses an antibody coupling drug targeting on EGFR, a preparation method thereof and uses thereof. The antibody-conjugated drug targeting EGFR is named LR004-VC-MMAE consisting of anantibody, a cytotoxic drug and a linker, wherein the antibody drug conjugate has a structure represented by the formula I, wherein mAb is an LR004 monoclonal antibody, n=2-8. The novel antibody-conjugated drug LR004-VC-MMAE can not only target EGFR antigen, but also has strong cytotoxicity to tumor cells. Compared with LR004 itself, it did not affect the affinity, endocytosis and targeting of theantibody, and better retained its biological function. Compared to LR004, the antitumor effect of LR004-VC-MMAE antibody-conjugated drug is significantly improved, and the tumor disappeared. Comparedto LR004, LR004-VC-MMAE antibody-conjugated total antibody showed longer half-life, slower clearance rate, lower concentration of free MMAE in plasma, shorter half-life and faster clearance rate, which is conducive to reduce toxicity.

PROCESS FOR THE PREPARATION OF DRUG LINKER COMPOUNDS

This disclosure generally relates to novel processes for the preparation of drug linker compounds and compositions comprising such drug linker compounds. The presently disclosed methods for synthesizing Fmoc-Val-Cit-PABOH and related compounds have also been found to minimize formation of diastereomeric impurities.

Cysteine transformation-based antibody-toxin conjugate

Heavy chain 235-site serine (S) and light chain 205-site valine (V) of a target antibody are transformed into cysteine (C), and after transformation, free sulfhydryl (-SH) of the cysteine is coupled to a mc-vc-PAB-OH connexon coupled with small molecular high-activity cytotoxin (Payload) in a fixed-point way to form a cysteine transformation-based antibody-toxin conjugate with good uniformity; thetoxin-antibody ratio (DAR) of the cysteine transformation-based antibody-toxin conjugate is 3.2-4.0, and the antibody-toxin conjugate adopts a general formula of 1C7-HC-S235C-LC-V205C-mc-vc-PAB-payload. The invention further discloses a preparation method and a purification method of a TDC medicine and application to treatment of EGFRwt (wild-type epidermal growth factor receptor) overexpressionrelated tumors.

Discovery of Peptidomimetic Antibody-Drug Conjugate Linkers with Enhanced Protease Specificity

Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity. Here we report the structure-guided discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing linker is hydrolyzed predominantly by cathepsin B while the valine-citrulline dipeptide linker is not. ADCs bearing the nonpeptidic linker are as efficacious and stable in vivo as those with the dipeptide linker. Our results strongly support the application of the peptidomimetic linker and present new opportunities for improving the selectivity of ADCs.

Cysteine-transformed antibody-toxin conjugate and its preparation method

The invention discloses a cysteine-transformed antibody-toxin conjugate and its preparation method. The cysteine-transformed antibody-toxin conjugate with excellent uniformity is formed by inserting aheavy chain and a light chain of a target antibody to the cysteine (C) at the fixed point, and performing fixed-point coupling on a free sulfydryl (-SH) of the cysteine inserted at the fixed point and a connector coupled with micromolecular high-activity cell toxin. The insert site of the cysteine disclosed in the invention is the 205th site and/or the 206th site (Kabat number) of the antibody light chain, and/or the 439th site of the heavy chain (Kabat number).

Cysteine engineered antibody - toxin conjugate (TDC) fixed-point coupling site screening (by machine translation)

The invention discloses a cysteine engineered antibody - toxin conjugate, characterized in that the antibody is the antibody fixed-point inserted cysteine, cysteine insertion site comprises a site selected from the following group of one or more of: light chain constant region of the light chain kappa / λ 110 position, section 111 position, section 142 bit, IgG antibody heavy chain constant region of the heavy chain of the 254 bit, of the 255 bit, of the 258 position, section 259 bit, section 354 bit, section 355 bit, part 357 bit, paragraph 378 bit, article 379 bit, section 386 bit, article 387 bit or 410 bit. (by machine translation)

NOVEL AURISTATIN DERIVATIVES AND RELATED ANTIBODY-DRUG CONJUGATES (ADCS) AND METHODS OF PREPARATION THEREOF

A compound according to the general Formula (8): wherein R1 is hydrogen or C1-C4 alkyl; R2 is C1-C4 alkyl, benzyl, or 1H-indol-3-ylmethyl; T is selected from the group consisting of -CH(OR3)-R4, -C(=O)-OR3, or -C(=O)-NR3 R5, wherein R3 is hydrogen or C1-C4 alkyl; R4 is phenyl; R5 is hydrogen or C1-C4 alkyl; L1 is R6-C(=O)-R7; where R6 is C1-C6 alkyl; R7 is a bond or NH-NH; L2 is a bond,, or; where n is 1-4; and Ab is an antibody or antigen-binding antibody fragment, and a process for preparing the same. In certain embodiments, Ab is an antibody or antigen-binding antibody fragment which binds to C4.4a.