- Linker, Antibody-Drug Conjugate Including Same and Use Thereof
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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 0454-0456; 0469; 0470
(2021/08/27)
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- Development of bifunctional anti-PD-L1 antibody MMAE conjugate with cytotoxicity and immunostimulation
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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
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- Synthesis, characterization, and targeted chemotherapy of SCT200-linker-monomethyl auristatin E conjugates
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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
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- ANTIBODY-DRUG CONJUGATE
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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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- CYCLIC DINUCLEOTIDE STING AGONISTS TETHERED TO A PD-1 OR CTLA-4 ANTIBODIES
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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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Page/Page column 132-133; 135-136
(2021/03/13)
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- PARA-AMINO-BENZYL LINKERS, PROCESS FOR THEIR PREPARATION AND THEIR USE IN CONJUGATES
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The present invention relates to para-amino-benzyl linker compounds useful for linking drug moieties to antibodies, to linker-drug compounds in which said para-amino-benzyl linker compounds are covalently linked to drug moieties, and to antibody-drug conjugates in which said para-amino-benzyl linker compounds are covalently linked to drug wherein said drug is enzymatically cleaved from the conjugate at a particular cell or tissue type targeted by said antibody.
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Page/Page column 64-65
(2021/11/26)
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- COMPOUNDS, COMPOSITIONS, METHODS, AND USES FOR TREATING CANCER AND IMMUNOLOGICAL DISORDERS
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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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- LINKERS AND CONJUGATES
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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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Page/Page column 48
(2020/02/23)
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- PRO-CYCLIC DINUCLEOTIDES AND PRO-CYCLIC DINUCLEOTIDE CONJUGATES FOR CYTOKINE INDUCTION
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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; 59; 75
(2019/07/17)
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- Unnatural amanitin type antibody conjugate
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The invention discloses unnatural amanitin type antibody conjugate. An unnatural amanitin as toxic as natural amanitins is conjugated with a biomolecule, which may combine with a target, through a bio-pharmaceutically acceptable connection structure so as to obtain a compound which is stable in plasma and which can effectively kill tumor cells in cells.
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- PROCESS FOR THE PREPARATION OF DRUG LINKER COMPOUNDS
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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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- Dual-sensitivity polymer-medicine connective and preparation method and application thereof
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The invention discloses a dual-sensitivity polymer-medicine connective and a preparation method and application thereof, and belongs to the fields of polymer chemistry and a pharmaceutical preparation. The method comprises the steps of preparing an enzyme sensitivity substrate into an enzyme sensitivity substrate intermediate; enabling medicines and cystamine dihydrochloride to be prepared into amedicine derivative containing disulfide bonds; enabling the enzyme sensitivity substrate and the medicine derivative to be connected to prepare a dual-sensitivity medicine derivative; and finally, condensing the methoxypolyethylene glycols and the medicine derivative to obtain the dual-sensitivity polymer-medicine connective being sensitive to glutathione reduction and tissue protease B. The dual-sensitivity polymer-medicine connective can be self-assembled to amphiphilic polymer micelle, connecting bonds are disulfide bonds and dipeptide, and the dual-sensitivity polymer-medicine connectivecan realize responsiveness crack at the tumor parts to release medicines. The invention further discloses the preparation method of an mPEG-VC-SS-GA copolymer and an application of the mPEG-VC-SS-GA copolymer as an antitumor medicine carrier.
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- An antibody-coupled drug targeting on EGFR, a preparation method thereof, and uses thereof
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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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Paragraph 0051; 0063; 0066
(2019/01/24)
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- Cysteine-transformed antibody-toxin conjugate and its preparation method
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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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Paragraph 0070; 0071; 0072
(2018/03/25)
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- HDAC INHIBITORS-BASED ANTIBODY DRUG CONJUGATES (ADCs) AND USE IN THERAPY
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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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- Cysteine engineered antibody - toxin conjugate (TDC) fixed-point coupling site screening (by machine translation)
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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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- Development and properties of valine-alanine based antibody-drug conjugates with monomethyl auristatin E as the potent payload
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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
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- DRUG-LINKER CONJUGATE PHARMACEUTICAL COMPOSITIONS
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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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Paragraph 000184-000186
(2017/05/02)
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- BENZOSELNOPHENE-BASED COMPOUND AND ANTIBODY-DRUG CONJUGATE CONTAINING THE SAME
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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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Paragraph 0428-0429
(2017/08/02)
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- BIFUNCTIONAL CYTOTOXIC AGENTS CONTAINING THE CTI PHARMACOPHORE
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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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Paragraph 0379; 0381
(2016/10/11)
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- Development of Anilino-Maytansinoid ADCs that Efficiently Release Cytotoxic Metabolites in Cancer Cells and Induce High Levels of Bystander Killing
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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.
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p. 2261 - 2278
(2015/12/01)
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- HYDROPHILIC LINKERS AND THEIR USES FOR CONJUGATION OF DRUGS TO CELL BINDING MOLECULES
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Cell binding agent-drug conjugates comprising hydrophilic linkers, and methods of using such linkers and conjugates are provided.
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- Novel cathepsin B-sensitive paclitaxel conjugate: Higher water solubility, better efficacy and lower toxicity
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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
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p. 618 - 629
(2012/10/07)
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- TARGETED POLYMERIC PRODRUGS CONTAINING MULTIFUNCTIONAL LINKERS
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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 78
(2008/06/13)
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