cas 159858-22-7, FMoc-Val-Cit-PAB | Articles data

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Synthesis, characterization, and targeted chemotherapy of SCT200-linker-monomethyl auristatin E conjugates
Antibody-drug conjugates (ADCs) are currently among the most successful and important strategies for treating patients with solid tumors. ADCs are composed of a monoclonal antibody and warhead, which are conjugated via a linker. Currently, monomethyl auristatin E (MMAE) is the most widely applied warhead in the development of ADCs. However, MMAE-based ADCs are generally constructed using the MC-VC-PABC linker, and this design has limited structural diversity and some disadvantages. Accordingly, in this study, we generated three types of novel linker-MMAE (with alterations in the spacer, catabolizing area, and self-immolative compared with MC-VC-PABC-MMAE) in ADCs, termed SCT200-linker-MMAE conjugates, and then evaluated the linker-drug plasma stability and the rate of drug release by cathepsin B. The binding ability, internalization rates, and efficacy of all SCT200-linker-MMAE ADCs were systematically studied, and the expression of apoptosis-associated proteins and the therapeutic efficacies of SCT200-M-2, -C-2, and -C-4 were evaluated. The results showed that the activities of some of these ADCs were increased for epidermal growth factor receptor-positive tumors. Moreover, the novel linkers designed in this study can be linked with other antibodies to treat other types of cancer. Overall, these findings provide important insights into the application of SCT200-based linkers in ADCs.
Hu, Xinyue,Jiang, Hailun,Bai, Weiqi,Liu, Xiujun,Miao, Qingfang,Wang, Linlin,Jin, Jie,Cui, Along,Liu, Rui,Li, Zhuorong
(2021/03/08)

CYCLIC DINUCLEOTIDE STING AGONISTS TETHERED TO A PD-1 OR CTLA-4 ANTIBODIES
Disclosed are antibody-drug conjugates and compositions thereof for the activation or induction of expression of a pattern recognition receptor (e.g., STING, RIG-I, MDA5), and methods of use thereof.
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(2021/03/13)

ANTIBODY-DRUG CONJUGATE
Provided herein is an antibody-drug conjugate (ADC) especially a PEGylated mono or bispecific antibody-drug conjugate (BsADC) prepared with site-specific conjugation to provide homogeneous conjugate with high potency and low toxicity. It also relates to a
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(2021/10/22)

A Wireframe DNA Cube: Antibody Conjugate for Targeted Delivery of Multiple Copies of Monomethyl Auristatin E
In recent years, several antibody drug conjugates (ADC) have been accepted by the FDA as therapeutics against cancer. It is well-known that control of drug-to-antibody ratio (DAR) is vital for the success of an ADC, which inspires the advancement of bette
Gothelf, Kurt V.,M?rcher, Anders,Nijenhuis, Minke A. D.
p. 21691 - 21696
(2021/09/02)

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.
Xiao, Dian,Luo, Longlong,Li, Jiaguo,Wang, Zhihong,Liu, Lianqi,Xie, Fei,Feng, Jiannan,Zhou, Xinbo
(2021/09/27)

Linker, Antibody-Drug Conjugate Including Same and Use Thereof
Provided are a linker represented by Formula I or I′, an antibody-drug conjugate containing the same, and use of thereof, a pharmaceutical composition comprising the antibody-drug conjugate, and use of the antibody-drug conjugate for treating and/or preventing a disease.
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Paragraph 0457; 0458; 0471; 0472

(2021/08/27)

PROTEIN-ANTIVIRAL COMPOUND CONJUGATES
Provided herein are compounds, compositions, and methods for the treatment of diseases and disorders associated with influenza, including VX-787 and derivatives thereof, baloxavir and derivatives thereof, and baloxavir marboxil and derivatives thereof, and protein (e.g., antibody) drug conjugates thereof.
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Paragraph 00181; 00187-00188

(2021/07/31)

LINKERS AND CONJUGATES
A conjugate comprising a protein or a peptide, a linker and an active agent, wherein the linker comprises the moiety of formula (III): (III) wherein two of A1, A2 and A3 are N and the other of A1, A2
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(2020/02/23)

COMPOUNDS, COMPOSITIONS, METHODS, AND USES FOR TREATING CANCER AND IMMUNOLOGICAL DISORDERS
The present disclosure provides novel polypeptide-therapeutic compound or hormone-therapeutic compound conjugates using cleavable or non-cleavable linkers, whereby the polypeptide or hormone serves to target specific cells using receptor expression on the targeted cell to bind the ligand (polypeptide or hormone) carrying the therapeutic compound unlike antibody drug conjugates. Upon binding, the ligand and the therapeutic compound (multiples of the therapeutic compound in some embodiments) enter the cell by receptor-mediated endocytosis, and release drugs conjugated to the ligand by linkers, to interact with intracellular components to enhance, restore, or block a signal transduction process. The ligands for the polypeptide-therapeutic compound or hormone-therapeutic compound conjugates include, but are not limited to: cytokines, growth factors and hormones among other proteins with corresponding cell surface specific receptors. The disorders targeted by such polypeptide-therapeutic compound or hormone-therapeutic compound conjugates include, but are not limited to: immunological disorders (e.g., allergy and autoimmune disorders) and cancer.
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(2020/02/06)

BIOACTIVE CONJUGATE, PREPARATION METHOD THEREFOR AND USE THEREOF
The disclosure relates to a bioactive molecule conjugate, preparation methods and use thereof, particularly relates to a novel bioactive molecule conjugate obtained by improving coupling of the drug and the targeting moiety in an ADC or SMDC, as well as its preparation method and use in the manufacture of a medicament for the treatment of a disease associated with an abnormal cell activity.
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Paragraph 0321-0322; 0328-0330

(2020/11/13)

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.
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(2019/01/24)

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.
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(2019/06/17)

PRO-CYCLIC DINUCLEOTIDES AND PRO-CYCLIC DINUCLEOTIDE CONJUGATES FOR CYTOKINE INDUCTION
The present invention provides a Pro-cyclic dinucleotide (Pro-CDN) comprising a STING agonist cyclic dinucleotide which is coupled to a linker system. The Pro-CDNs of the present invention can be metabolized at a targeted site into CDNs and exert their full immunomodulatory effects at said targeted site. The present invention also provides conjugates wherein a Pro-CDN is conjugated to a Biologically Active Molecule (BAM) such as e.g. a cytotoxic molecule, a lipid, a protein, a peptide, a nucleic acid, a sugar or a PRR ligand. The invention provides also methods related to the use of such compounds to perform their activities at their targeted sites, to exert cytotoxic, cytostatic or immunomodulatory effects, to treat or to prevent diseases such as cancers, immunological disorders or infections.
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Page/Page column 58; 60; 75

(2019/07/17)

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).
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(2018/03/25)

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)
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(2018/11/22)

Improved Methodology for the Synthesis of a Cathepsin B Cleavable Dipeptide Linker, Widely Used in Antibody-Drug Conjugate Research
Antibody-drug conjugates (ADCs) represent an emerging class of biopharmaceutical agents that deliver highly potent anticancer agents (payloads) selectively to tumors or components associated with the tumor microenvironment. The linker, responsible for the connection between the antibody and payload, is a crucial component of ADCs. In certain examples the linker is composed of a cleavable short peptide which imparts an additional aspect of selectivity. Especially prevalent is the cathepsin B cleavable Mc-Val-Cit-PABOH linker utilized in many pre-clinical ADC candidates, as well as the FDA approved ADC ADCETRIS (brentuximab vedotin). An alternative route for the synthesis of the cathepsin B cleavable Mc-Val-Cit-PABOH linker is reported herein that involved six steps from l-Citrulline and proceeded with a 50% overall yield. In this modified route, the spacer (a para-aminobenzyl alcohol moiety) was incorporated via HATU coupling followed by dipeptide formation. Importantly, this route avoided undesirable epimerization and proceeded with improved overall yield. Utilizing this methodology, a drug-linker construct incorporating a potent small-molecule inhibitor of tubulin polymerization (referred to as KGP05), was synthesized as a representative example.
Mondal, Deboprosad,Ford, Jacob,Pinney, Kevin G.
p. 3594 - 3599
(2018/09/11)

HDAC INHIBITORS-BASED ANTIBODY DRUG CONJUGATES (ADCs) AND USE IN THERAPY
The present invention relates to novel Histone Deacetylase Inhibitors (HDACi)- based antibody drug conjugates particularly with antibodies directed to ErbB1, ErbB2 and ErbB3 receptors, pharmaceutical compositions comprising said antibodies as well as to their use in the treatment of cancer or tumor and other diseases where a modulation of one or more histone deacetylase isoforms can be effective for therapeutic interventions.
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(2018/10/25)

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.
Wei, Binqing,Gunzner-Toste, Janet,Yao, Hui,Wang, Tao,Wang, Jing,Xu, Zijin,Chen, Jinhua,Wai, John,Nonomiya, Jim,Tsai, Siao Ping,Chuh, Josefa,Kozak, Katherine R.,Liu, Yichin,Yu, Shang-Fan,Lau, Jeff,Li, Guangmin,Phillips, Gail D.,Leipold, Doug,Kamath, Amrita,Su, Dian,Xu, Keyang,Eigenbrot, Charles,Steinbacher, Stefan,Ohri, Rachana,Raab, Helga,Staben, Leanna R.,Zhao, Guiling,Flygare, John A.,Pillow, Thomas H.,Verma, Vishal,Masterson, Luke A.,Howard, Philip W.,Safina, Brian
p. 989 - 1000
(2018/01/01)

DRUG-LINKER CONJUGATE PHARMACEUTICAL COMPOSITIONS
Compositions are disclosed having a cytotoxic and/or vascular disrupting agent (VDA) payload attached to a linker. The linker can be a cathepsin B protease cleavable linker or a non-cleavable linker that may degrade intracellularly. Methods for making and using the compositions are also provided. The compositions can be provided to a patient in need thereof with the composition coming into contact with a cancer cell to activate or release the cytotoxic and/or vascular disrupting agent payload.
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(2017/05/02)

BENZOSELNOPHENE-BASED COMPOUND AND ANTIBODY-DRUG CONJUGATE CONTAINING THE SAME
The present invention relates to a benzoselnophene-based compound, and a preparation method thereof, and antibody-drug conjugate (ADC) containing the benzoselnophene-based compound. The present invention provides the benzoselnophene-based compound or a sa
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(2017/08/02)

Development and properties of valine-alanine based antibody-drug conjugates with monomethyl auristatin E as the potent payload
Antibody-drug conjugates (ADCs), designed to selectively deliver cytotoxic agents to antigen-bearing cells, are poised to become an important class of cancer therapeutics. Human epithelial growth factor receptor (HER2) is considered an effective target for cancer treatment, and a HER2-targeting ADC has shown promising results. Most ADCs undergoing clinical evaluation contain linkers that have a lysosomal protease-cleavable dipeptide, of which the most common is valine-citrulline (VC). However, valine-alanine (VA), another dipeptide comprising two human essential amino acids, has been used in next generation ADCs loading new toxins, but the druggable properties of ADCs loaded the most popular monomethyl auristatin E (MMAE) remain to be further explored. In this study, we generated VA-based ADCs that connected MMAE to an anti-HER2 antibody. We studied the differences in the preparation process, in vitro stability, cathepsin B activity and in vitro cytotoxicity of VA-based ADC compared to the ADC of VC. VA had comparable performance to VC, which preliminarily displays its practicability. Additional efficacy and safety studies in a xenograft model indicate this novel ADC exerted potent anti-tumor activity and negligible toxicity. The results of this study show the application potential of VA-based ADC with MMAE as the payload.
Wang, Yanming,Fan, Shiyong,Zhong, Wu,Zhou, Xinbo,Li, Song
(2017/09/01)

A water-soluble nucleolin aptamer-paclitaxel conjugate for tumor-specific targeting in ovarian cancer
Paclitaxel (PTX) is among the most commonly used first-line drugs for cancer chemotherapy. However, its poor water solubility and indiscriminate distribution in normal tissues remain clinical challenges. Here we design and synthesize a highly water-solubl
Li, Fangfei,Lu, Jun,Liu, Jin,Liang, Chao,Wang, Maolin,Wang, Luyao,Li, Defang,Yao, Houzong,Zhang, Qiulong,Wen, Jia,Zhang, Zong-Kang,Li, Jie,Lv, Quanxia,He, Xiaojuan,Guo, Baosheng,Guan, Daogang,Yu, Yuanyuan,Dang, Lei,Wu, Xiaohao,Li, Yongshu,Chen, Guofen,Jiang, Feng,Sun, Shiguo,Zhang, Bao-Ting,Lu, Aiping,Zhang, Ge
(2017/11/20)

BIFUNCTIONAL CYTOTOXIC AGENTS CONTAINING THE CTI PHARMACOPHORE
The present invention is directed to novel bifunctional CTI-CTI and CBI-CTI dimers of the formula: [in-line-formulae]F1-L1-T-L2-F2 [/in-line-formulae] where F1, L1, T, L2 and F2 are as defined herein, useful for the treatment for proliferative diseases, where the inventive dimers can function as stand-alone drugs, payloads in antibody-drug-conjugates (ADCs), and linker-payload compounds useful in connection with the production or administration of such ADCs; and to compositions including the aforementioned dimers, linker-payloads and ADCs, and methods for using these dimers, linker-payloads and ADCs, to treat pathological conditions including cancer.
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(2016/10/11)

Development of Anilino-Maytansinoid ADCs that Efficiently Release Cytotoxic Metabolites in Cancer Cells and Induce High Levels of Bystander Killing
Antibody anilino maytansinoid conjugates (AaMCs) have been prepared in which a maytansinoid bearing an aniline group was linked through the aniline amine to a dipeptide, which in turn was covalently attached to a desired monoclonal antibody. Several such
Widdison, Wayne C.,Ponte, Jose F.,Coccia, Jennifer A.,Lanieri, Leanne,Setiady, Yulius,Dong, Ling,Skaletskaya, Anna,Hong, E. Erica,Wu, Rui,Qiu, Qifeng,Singh, Rajeeva,Salomon, Paulin,Fishkin, Nathan,Harris, Luke,Maloney, Erin K.,Kovtun, Yelena,Veale, Karen,Wilhelm, Sharon D.,Audette, Charlene A.,Costoplus, Juliet A.,Chari, Ravi V. J.
p. 2261 - 2278
(2015/12/01)

PEPTIDOMIMETIC COMPOUNDS AND ANTIBODY-DRUG CONJUGATES THEREOF
This invention relates to peptidomimetic linkers and anti-body drug conjugates thereof, to pharmaceutical compositions containing them, and to their use in therapy for the prevention or treatment of cancer.
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(2015/07/07)

HYDROPHILIC LINKERS AND THEIR USES FOR CONJUGATION OF DRUGS TO CELL BINDING MOLECULES
Cell binding agent-drug conjugates comprising hydrophilic linkers, and methods of using such linkers and conjugates are provided.
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(2014/06/11)

Novel cathepsin B-sensitive paclitaxel conjugate: Higher water solubility, better efficacy and lower toxicity
In order to realize the targeted delivery of paclitaxel (PTX) to tumor through an environment-sensitive mechanism, increase its solubility in water and reformulate without toxic excipients, a novel PTX conjugate, PEG-VC-PABC-PTX was designed and synthesiz
Liang, Liang,Lin, Song-Wen,Dai, Wenbing,Lu, Jing-Kai,Yang, Ting-Yuan,Xiang, Yu,Zhang, Yang,Li, Run-Tao,Zhang, Qiang
p. 618 - 629
(2012/10/07)

TARGETED POLYMERIC PRODRUGS CONTAINING MULTIFUNCTIONAL LINKERS
The present invention provides single chain antibody-directed polymeric prodrugs containing multifunctional linkers. Methods of making the polymeric delivery systems and methods of treating mammals using the same are also disclosed.
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Page/Page column 79

(2008/06/13)