- Photopolymerization of maleimide perfluoropolyalkylethers without a photoinitiator
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Perfluoropolyalkylethers derived from hexafluoropropylene oxide were functionalized with maleimide groups. Irradiated by UV-light, the new maleimide macromonomers demonstrated very fast polymerization kinetics with a curing time as fast as 8 s. The effect on photopolymerization of different features such as the molecular weight of the fluorinated chain and the chain length of the hydrogenated spacer were studied, as well as the influence of the type of photoinitiator and the presence of air. Thermal and surface properties of the UV-cured polymers were examined and were typical to fluoropolymers in view of water–oil repellent coatings.
- Bonneaud, Céline,Burgess, Julia M.,Bongiovanni, Roberta,Joly-Duhamel, Christine,Friesen, Chadron M.
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Read Online
- Preparation of a New PEGylation Reagent for Sulfhydryl-containing Polypeptide
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N-maleimido-6-amino-caproyl ester of PEG was preparated in the presence of DCC etc., as a new sulfhydryl-PEGylation reagent substituted for mal-sac-PEG.
- Wei tang,Chang, Yuan,Liu, Xin-Yuan
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Read Online
- Multifunctional Tumor-Targeting Cathepsin B-Sensitive Gemcitabine Prodrug Covalently Targets Albumin in Situ and Improves Cancer Therapy
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We report a new type of amide bond-bearing cathepsin B-sensitive gemcitabine (GEM) prodrugs, capable of in situ covalently targeting circulating albumin and then making a hitchhike to the tumor. Specially, less plasma-enzyme deactivation, long plasma half-life, independence on nucleoside transporters, outstanding tumor targeting, and site-specific drug release are achieved, and as such these multifunctional advantages contribute to the dramatically increased in vivo antitumor efficacy.
- Zhang, Huicong,Sun, Zhisu,Wang, Kuanglei,Li, Na,Chen, Hongxiang,Tan, Xiao,Li, Lingxiao,He, Zhonggui,Sun, Jin
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Read Online
- Novel fatty acid chain modified GLP-1 derivatives with prolonged in vivo glucose-lowering ability and balanced glucoregulatory activity
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Glucagon-like peptide-1 is a potent hypoglycemic hormone with beneficial properties for the treatment of diabetes. However, its half-life is short because the rapid metabolic degradation. This study aims to prolong the half-life of glucagon-like peptide-1 through conjugation with the fatty acid side chain which helps the conjugates to interact with the albumin. Firstly, we chose two optimized polypeptide chains which have tremendous hypoglycemic effect named Cys17-Gly8-GLP-1(7-36)-NH2 and Cys37-Gly8-GLP-1(7-37)-NH2, and various fatty acid chains were modified. All conjugates preserved relatively strong GLP-1R activation and I-6 behaved best in glucose-lowering ability. The prolonged antidiabetic effects of I-6 were further confirmed by hypoglycemic efficacy test in vivo. Meanwhile, once daily injection of I-6 to diabetic mice achieved long-term beneficial effects on glucose tolerance, body weight and blood chemistry. It is concluded that I-6 is a promising agent for further investigation of its potential to treat obese patients with diabetes.
- Cai, Xingguang,Sun, Lidan,Dai, Yuxuan,Avraham, Yosefa,Liu, Chunxia,Han, Jing,Liu, Yuan,Feng, Dazhi,Huang, Wenlong,Qian, Hai
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Read Online
- Cytosine arabinoside prodrug designed to bind plasma serum albumin for drug delivery
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Rational design of anticancer prodrugs for efficient albumin binding can show distinct advantages in drug delivery in terms of high drug availability, long systemic circulation, potential targeting effect, and enhanced chemotherapy effect. In the present study, we reported a cytosine arabinoside (Ara-C) prodrug which could well formulate in solution and instantly transform into long-circulating nanocomplexes by hitchhiking blood-circulating albumin after i.v. administration. Specifically, Ara-C was conjugated with an albumin-binding maleimide derivative, the resulting Ara-C maleimide caproic acid conjugate (AM) was well formulated in aqueous solution, conferring high albumin-binding ability in vitro albumin-binding studies. Moreover, in vivo fluorescence images of sulfo-cyanine5 maleimide indirectly demonstrated that AM showed better accumulation in tumors, exhibiting superior tumor targeting ability and antitumor activity compared to Ara-C. Such a uniquely developed strategy, integrating high albumin-binding capability, has great potential to be applied in clinical cancer therapy.
- Wei, Wei,He, Zhonggui,Yang, Jincheng,Sun, Mengchi,Sun, Jin
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Read Online
- 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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- 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 0532; 0533
(2021/08/27)
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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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supporting information
(2021/03/08)
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- A designed cyclic peptide based on Trastuzumab used to construct peptide-drug conjugates for its HER2-targeting ability
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Human epidermal growth factor receptor 2 (HER2) has been recognized as an important therapeutic target for its overexpression in many cancers. Trastuzumab is a monoclonal antibody targeting HER2, which has been approved by FDA to treat HER2-positive cancer. In this research, cyclic peptide Cyclo-GCGPep1 was designed based on the binding mode between antibody and HER2 protein in silico, which has been confirmed possessing good affinity with HER2. Cyclo-GCGPep1 was also used to construct peptide-drug conjugates with Camptothecin. Biological evaluations demonstrated that Conjugate 1 has a good antiproliferative activity on SK-BR-3 and NCI-N87 cells. Conjugate 1 retained the pro-apoptotic and Topo I inhibitory ability of Camptothecin. Meanwhile, it has good targeting ability towards HER2-positive cells with the help of Cyclo-GCGPep1. It also has better permeability in the tumor spheroid model than Camptothecin. In summary, the design of cyclic peptide derived from antibody is of significance for the discovery of targeting peptides and Conjugate 1 is expected as a good therapeutic agent for HER2-positive cancers.
- Zhou, Jiaqi,Zou, Yuxing,Cai, Yan,Chi, Fanglian,Huang, Wenlong,Shi, Wei,Qian, Hai
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- Antibody-drug conjugate using ionized CYS-linker-mmae as the potent payload shows optimal therapeutic safety
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Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced “bystander effect” inevitably increase the toxicity to normal tissues. Herein, we overturn previous negative views of MMAE-based ADCs with non-cleavable linkers and propose using ionized L-Cysteine (Cys)-linker-MMAE as a novel payload, which can ingeniously enrich and enter tumor cells through receptor-mediated endocytosis of antibodies while its lower permeability helps to avoid further off-target toxicity. We demonstrate that Cys-linker-MMAE maintains high potency similar to free MMAE at the tubulin molecular level and can also be efficiently released in target cells. As a result, the preferred ADC (mil40-15) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC50: 10?11 M), but also shows improved safety with lower bystander toxicity (IC50: 10?9 M), its maximum tolerated dose approaching the level of the naked antibody (160 mg/kg). This study indicated that Cys-linker-MMAE has the potential as a potent payload for ADCs, which is expected to provide novel strategies for the development of MMAE-based ADCs.
- Fan, Shiyong,Li, Wei,Liu, Lianqi,Wang, Yanming,Xiao, Dian,Xie, Fei,Zhong, Wu,Zhou, Xinbo
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- Elastic targeting polypeptide-based medicine-carrying nanoparticle as well as preparation method and application thereof
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The invention discloses an elastic targeting polypeptide-based medicine-carrying nanoparticle. The nanoparticle is prepared from an elastic targeting polypeptide and a modified medicine, wherein the modified medicine is a modified paclitaxel PTX-LEV-MECH or modified salinomycin Sail-ABA-MPBH. The elastic targeting polypeptide-based medicine-carrying nanoparticle provided by the invention is 100nmor below in particle size, so that the dispersion degree is low, the medicine carrying rate is high, and the nanoparticle can be combined with in-vivo albumin for transferring and carrying medicine, and also can be combined with acidic rich cysteine specifically secreted by tumor cells, the drug is concentrated in the acidic environment, the breast cancer in-situ cancer is targeted for killing, and the toxic and side effects of the drug on the whole body are reduced; and the efficacy of treating breast cancer is increased and improved by utilizing the synergistic effect of two nanoparticles, the occurrence of the metastasis of the breast cancer cells through a lymphatic system and a blood system is reduced, and the occurrence of serious complications such as medical-source lymphatic edemacaused by a lymph node sweeping surgery is reduced.
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Paragraph 0029; 0030; 0032
(2020/07/15)
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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 0061; 0062; 0063
(2018/03/25)
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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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Paragraph 0004; 0005; 0006
(2018/11/22)
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- Cysteine transformation-based antibody-toxin conjugate
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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.
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Paragraph 0008-0010
(2018/11/22)
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- Maleimide prodrug having biological adhesion effect and application of maleimide prodrug in oral medicine transmission
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The invention belongs to the technical field of medicine, and relates to a maleimide prodrug taking mucoprotein as a target point in promotion of biological adhesion and an application of the maleimide prodrug in increasing of oral drug absorption. The maleimide prodrug has a structural formula shown in a formula (I): wherein n is 2-8, and X is O, N. The prodrug has the advantages of high compounddrug loading, good stability, and safety, and can be used for oral administration. The carried maleimide group can be specifically combined with mucoprotein in a mucous layer in gastrointestinal tract, a mucoprotein-prodrug compound is formed, detention time of the prodrug in the gastrointestinal tract is prolonged, concentration gradient of an adsorption-absorption part is increased, passive diffusion is promoted, and oral absorption is promoted. The invention provides the novel maleimide prodrug having the biological adhesion effect for oral absorption of the drug.
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Paragraph 0037; 0038; 0039
(2018/07/07)
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- Active custom white [...] drug delivery carrier and its use in pharmacy (by machine translation)
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The invention belongs to the pharmaceutical preparation of the new materials and new formulation field, relates to in order to endogenous white protein as the target of the drug delivery system design and application. The use of active custom white [...] carrier material, in order to maleic imide as a target head, polyethylene glycol as the flexibility of the [...] connected to flay, hydrophobic material (such as PLGA, such as stearic acid) as the anchoring part. This carrier material preparation of nano delivery formulation can be entrapped a plurality of anti-tumor drug, and can through its surface maleimide active combined [...], tumor blood vessel and tumor cells with high expression of albumin receptor (SPARC, gp60) interaction, overcome the various biological transfer barrier, effectively improve the nano particles accumulating in tumor site of, tumor cell uptake and anti-tumor activity. The nano-delivery formulation stability is good, high safety, target best, can be used for intravenous injection, large market application prospect. (by machine translation)
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Paragraph 0018; 0021; 0056-0059; 0062-0064
(2018/08/03)
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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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Page/Page column 58-60
(2018/10/25)
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- SILVESTROL ANTIBODY-DRUG CONJUGATES AND METHODS OF USE
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The invention relates generally to a silvestrol molecule activated with a leaving group. The invention further relates generally to an antibody-drug conjugate comprising an antibody conjugated by a linker to one or more silvestrol drug moieties and methods of treatment.
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Page/Page column 81
(2018/01/15)
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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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- Legumain Activated Doxorubicin Derivative as well as Preparation Method and Application Thereof
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The present invention discloses doxorubicin derivatives for targeted activation by Legumain, its preparation method and use. The doxorubicin derivatives are obtained by condensation between the amino group of compound A and the carboxyl group of compound B and have the following structure: compounds A and B have the following structures, respectively: wherein R3 in compound B is Leu or absent; R4 is any one amino acid selected from the group consisting of Ala and Thr; R5 is any one amino acid selected from the group consisting of Ala, Thr and Asn; R6 is wherein n=1-20; or wherein R7 is substituted or unsubstituted, linear or branched, saturated or unsaturated C1-C20 fatty hydrocarbon, or substituted or unsubstituted C6-C20 aromatic hydrocarbon. The doxorubicin derivatives of the present invention are specifically tumor-targeted and have a long in vivo metabolic half-life, as compared with doxorubicin. They exhibit an efficient and safe anti-tumor effect and could be used to prepare an anti-tumor drug.
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Paragraph 0066
(2017/05/07)
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- Synthesis and applications of an albumin bounding type 5-fluorouracil prodrug
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The invention relates to an albumin bounding type 5-fluorouracil prodrug, and applications thereof in anti-tumor drug transfer. The prodrug is a compound formed by bridging 4-maleimidobutyric acid, 6-maleimidocaproic acid or 8-maleimido octanoic acid and N1-hydroxymethyl-5-fluorouracil through an ester bond, wherein the maleimido group is adopted as a bonding target of free sulfydryl of 34-site cysteine of albumin. The prodrug compound can be rapidly specifically bonded with albumin in blood to form an albumin prodrug composite, and therefore the drug metabolism speed is reduced, drug half life is significantly prolonged, and a long circulation function is achieved. In addition, under EPR effects and albumin acceptor mediation, tumor targeting is achieved and antitumor effects are improved. The 5-fluorouracil prodrug is used for intravenous injection and has a wide market application prospect.
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Paragraph 0034; 0035; 0036
(2017/08/28)
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- QUATERNARY AMINE COMPOUNDS AND ANTIBODY-DRUG CONJUGATES THEREOF
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This invention relates to antibody-drug conjugates represented by Formula (I) Ab- (L-D)p, Ab is an antibody; p is 1-8; L-D is a chemical moiety represented by the following formula -Str-(Pep)-Sp-D; Str is a stretcher unit covalently attached to Ab; Pep is a linker; D is anti-tumor agent represented by the following formula wherein Rand Rare each independently Ct-C6alkyl, and Ris a non-hydrogen substituent; or Ris C1-C6alkyl, and Rand Rtogether with the N form a substituted C3-C7heterocycloalkyl ring; or R° is absent, and Rand Rtogether with the N form a substituted heteroaryl ring; Sp-D is a spacer moiety of fomula: This invention also relates to a method of treating cancer, use of antibody-drug conjugates of Formula (I) in therapy, and use of antibody-drug conjugates of Formula (I) in manufacturing a medicament for treating cancer. This invention also relates to method of preparing antibody-drug conjugates of Formula (I).
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Page/Page column 61-62
(2016/06/28)
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- ANTI-STAPHYLOCOCCUS AUREUS ANTIBODY RIFAMYCIN CONJUGATES AND USES THEREOF
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The invention provides anti-Staphylococcus aureus antibody rifamycin antibiotic conjugates and methods of using same.
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Page/Page column 123
(2016/06/28)
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- ANTI-STAPHYLOCOCCUS AUREUS ANTIBODY RIFAMYCIN CONJUGATES AND USES THEREOF
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The invention provides rF1 antibody antibiotic conjugates and methods of using same.
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Page/Page column 89
(2016/06/28)
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- ANTIBODIES AND IMMUNOCONJUGATES
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The invention provides immunoconjugates and methods of using the same.
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Paragraph 00337; 00338
(2017/01/02)
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- CYTOTOXIC AND ANTI-MITOTIC COMPOUNDS, AND METHODS OF USING THE SAME
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Compounds having cytotoxic and/or anti-mitotic activity are disclosed. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed. Also disclosed are compositions having the structure: (T)-(L)-(D), wherein (T) is a targeting moiety, (L) is an optional linker, and (D) is a compound having cytotoxic and/or anti-mitotic activity.
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Page/Page column 97
(2016/04/09)
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- PEPTIDOMIMETIC COMPOUNDS AND ANTIBODY-DRUG CONJUGATES THEREOF
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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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Page/Page column 67
(2015/07/07)
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- PEPTIDOMIMETIC COMPOUNDS AND ANTIBODY-DRUG CONJUGATES THEREOF
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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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Page/Page column 261; 262
(2015/07/07)
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- SULFONAMIDE-CONTAINING LINKAGE SYSTEMS FOR DRUG CONJUGATES
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Sulfonamide-containing linkage systems for release of payload compounds from an attached targeting moiety in drug conjugates. The conjugates have the formula of [(P)-(L)]m-(T), wherein (P) is a payload compound, (L) is a linker, (T) is a targeting moiety and m is an integer from 1- to 10. Also provided are pharmaceutical compositions comprising such conjugates and there use in treating cancer.
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Page/Page column 118
(2015/07/15)
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- SYNTHESIS OF NOVEL ASYMMETRIC BOW-TIE PAMAM DENDRIMER-BASED CONJUGATES FOR TUMOR-TARGETING DRUG DELIVERY
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The present disclosure relates to a dendrimer-based conjugate of the formula Vm-D-C-D'-(T-F)n, which is useful for tumor targeting drug delivery. The use of asymmetric dendrimers allow for specific targeting as well as synthetic reproducibility.
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Paragraph 0076
(2015/03/28)
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- Active immunisation of mice with GnRH lipopeptide vaccine candidates: Importance of T helper or multi-dimer GnRH epitope
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Active immunisation against gonadotropin releasing hormone (GnRH) is a potential alternative to surgical castration. This study focused on the development of a GnRH subunit lipopeptide vaccine. A library of vaccine candidates that contained one or more (up to eight) copies of monomeric or dimeric GnRH peptide antigen, an adjuvanting lipidic moiety based on lipoamino acids, and an additional T helper epitope, was synthesised by solid phase peptide synthesis. The candidates were evaluated in vivo in order to determine the minimal components of this vaccine necessary to induce a systemic immune response. BALB/c mice were immunised with GnRH lipopeptide conjugates, co-administered with or without Complete Freund's Adjuvant, followed by two additional immunisations. Significant GnRH-specific IgG titres were detected in sera obtained from mice immunised with four of the seven lipopeptides tested, with an increase in titres observed after successive immunisations. This study highlights the importance of for epitope optimisation and delivery system design when producing anti-hapten antibodies in vivo. The results of this study also contribute to the development of future clinical and veterinary immunocontraceptives.
- Goodwin, Daryn,Simerska, Pavla,Chang, Cheng-Hung,Mansfeld, Friederike M.,Varamini, Pegah,D'Occhio, Michael J.,Toth, Istvan
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p. 4848 - 4854
(2014/11/07)
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- Next generation maleimides enable the controlled assembly of antibody-drug conjugates via native disulfide bond bridging
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The advent of Adcetris and Kadcyla, two recently FDA-approved antibody-drug conjugates (ADCs), in the clinic has had a major impact on the treatment of lymphoma and breast cancer patients, respectively, worldwide. Despite these successes many new ADCs fail at various stages of development, often due to shortcomings in the methods used for their assembly. To address this problem we have developed next generation maleimides (NGMs), which specifically re-bridge reduced interchain disulfide bonds and allow the efficient conjugation of small molecules to antibodies, without the need for engineering of the target antibody. The method is site-specific and generates near homogeneous products in good yields. Moreover, adjustment of the reaction conditions allows control of the conjugation in terms of stoichiometry (drug-loading) and site selectivity. Using this method we prepared a series of ADCs from trastuzumab and doxorubicin (DOX) with a controlled drug-to-antibody ratio (DAR) of 1, 2, 3 and 4. All of these constructs were fully active by ELISA and had more than 90% of re-bridged disulfide bonds by CE-SDS when compared to clinical grade antibody. Furthermore, digest experiments of the DAR 2 material revealed that almost all of the drug had been targeted to the Fab arms of the antibody. Thus, NGMs offer a flexible and simple platform for the controlled assembly of ADCs from an antibody. This journal is the Partner Organisations 2014.
- Schumacher, Felix F.,Nunes, Joao P. M.,Maruani, Antoine,Chudasama, Vijay,Smith, Mark E. B.,Chester, Kerry A.,Baker, James R.,Caddick, Stephen
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supporting information
p. 7261 - 7269
(2014/11/07)
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- Azide-alkyne cycloaddition for universal post-synthetic modifications of nucleic acids and effective synthesis of bioactive nucleic acid conjugates
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The regioselective post-synthetic modifications of nucleic acids are essential to studies of these molecules for science and applications. Here we report a facile universal approach by harnessing versatile phosphoramidation reactions to regioselectively incorporate alkynyl/azido groups into post-synthetic nucleic acids primed with phosphate at the 5′ termini. With and without the presence of copper, the modified nucleic acids were subjected to azide-alkyne cycloaddition to afford various nucleic acid conjugates including a peptide-oligonucleotide conjugate (POC) with high yield. The POC was inoculated with human A549 cells and demonstrated excellent cell-penetrating ability despite cell deformation caused by a small amount of residual copper chelated to the POC. The combination of phosphoramidation and azide-alkyne cycloaddition reactions thus provides a universal regioselective strategy to post-synthetically modify nucleic acids. This study also explicated the toxicity of residual copper in synthesized bioconjugates destined for biological systems. This journal is the Partner Organisations 2014.
- Su, Yu-Chih,Lo, Yu-Lun,Hwang, Chi-Ching,Wang, Li-Fang,Wu, Min Hui,Wang, Eng-Chi,Wang, Yun-Ming,Wang, Tzu-Pin
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p. 6624 - 6633
(2014/08/18)
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- CHEMICAL CROSSLINKERS AND COMPOSITIONS THEREOF
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Chemical crosslinkers and methods of their synthesis are disclosed.
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Paragraph 0214; 0218
(2014/09/16)
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- Design, synthesis, and biological activity of novel dicoumarol glucagon-like peptide 1 conjugates
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Twelve novel dicoumarol glucagon-like peptide 1 (GLP-1) conjugates were designed, synthesized, and tested for biological activity. All derivatives retained receptor activation efficacy, and exhibited improved albumin affinity and in vitro stability in rat plasma. The in vivo elimination half-lives of 13c and 13l (22.07 and 18.78 h, respectively) were much longer than those of the GLP-1 receptor agonists exendin-4 (2.82 h) and liraglutide (12.53 h). The prolonged in vivo antidiabetic effects of 13c and 13l on db/db mice were confirmed by the hypoglycemic efficacy test and the multiple intraperitoneal glucose tolerance test. Importantly, a once daily administration of 13c to db/db mice for 7 weeks provided long-term beneficial effects by lowering glycated hemoglobin (HbA1c) levels to 5.05%, which was lower than with liraglutide treatment (5.41%). These results suggest that 13c is a promising long-lasting GLP-1 mimetic that may be suitable for clinical use following further research.
- Han, Jing,Sun, Lidan,Chu, Yingying,Li, Zheng,Huang, Dandan,Zhu, Xiaoyun,Qian, Hai,Huang, Wenlong
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p. 9955 - 9968
(2014/01/17)
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- ANTIBODY-DRUG CONJUGATES AND RELATED COMPOUNDS, COMPOSITIONS, AND METHODS
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Antibody-cytotoxin antibody-drug conjugates and related compounds, such as linker- cytotoxin conjugates and the linkers used to make them, tubulysin analogs, and intermediates synthesis; compositions; and methods, including methods of treating cancers.
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Paragraph 0059-0061
(2013/06/27)
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- Coatings for medical articles including natural biodegradable polysaccharides
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Biodegradable coatings that include natural biodegradable polysaccharides are described. The coating is formed from a plurality of natural biodegradable polysaccharides having pendent coupling groups.
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- Cancer-targeting antibody-drug conjugates: Site-specific conjugation of doxorubicin to anti-EGFR 528 Fab′ through a polyethylene glycol linker
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Antibodydrug conjugates have been prepared to examine the effect that attaching small-molecule drugs to an antibody fragment has on antibody activity. The anticancer drug doxorubicin was covalently attached through a polyethylene glycol linker to a cancer-targeting, anti-epidermal growth factor receptor antibody fragment (Fab′). The reactivity of maleimide was compared with a substituted maleimide derivative (citraconimide) in conjugation reactions with cysteine residues on a Fab′. Introduction of polyethylene glycol increased aqueous solubility of the cytotoxic drug, which led to an improvement in overall yield of the conjugation reaction with the antibody fragment. Antibodydrug conjugates prepared retained activity of the parent antibody, as determined by antigen binding experiments measured by surface plasmon resonance.
- Hong, Lisa P. T.,Scoble, Judith A.,Doughty, Larissa,Coia, Gregory,Williams, Charlotte C.
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experimental part
p. 779 - 789
(2012/07/14)
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- Practical synthesis of maleimides and coumarin-linked probes for protein and antibody labelling via reduction of native disulfides
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The cellular tracking, detection and sensing of protein or antibody movement are important aspects to advance our understanding of biomolecular interactions and activity. Antibodies modified with fluorescent dyes are also valuable tools, especially in immunology research. We describe here a proof-of-principle study of a new water-soluble coumarin probe with a maleimide thiol-reacting unit to fluorescently tag biomolecules. Highlights include: (1) a convenient water-based preparation of N-substituted maleimides, (2) a one-pot preparation of activated maleimido-esters, and (3) a bio-conjugation protocol for the selenol-promoted reduction of native disulfide bonds and the 'site-specific' labelling of antibodies with no significant loss of activity.
- Song, Hong Y.,Ngai, Mun H.,Song, Zhen Y.,MacAry, Paul A.,Hobley, Jonathan,Lear, Martin J.
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experimental part
p. 3400 - 3406
(2010/01/06)
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- Biodegradable ocular implants and methods for treating ocular conditions
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Biodegradable ocular implants are described. The ocular implants include a bioactive agent that can be released within the eye to treat an ocular condition or indication. The implants can be used for the administration of a bioactive agent over prolonged periods of time. In some aspects the implants are formed of a matrix of natural biodegradable polysaccharides.
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- Synthesis of 4-maleimidobutyric acid and related maleimides
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Maleimidoalkanoic acids and their activated derivatives, such as their N-hydroxysuccinimide esters, are important, though expensive, linkers for the conjugation of biomolecules. During our synthesis of UCS1025A, we have developed a chromatography-free preparation of 4-maleimidobutyric acid on a one-mole scale. Georg Thieme Verlag Stuttgart.
- De Figueiredo, Renata Marcia,Oczipka, Philipp,Froehlich, Roland,Christmann, Mathias
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p. 1316 - 1318
(2008/12/22)
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- Tissue graft materials containing biocompatible agent and methods of making and using same
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The invention provides implantable tissue graft materials composed of a collagenous tissue scaffold and a biocompatible agent bonded to the tissue scaffold via an activated photoreactive group. The invention further provides methods including steps of obtaining a tissue graft material comprising a collagenous tissue scaffold; contacting the collagenous tissue scaffold with a biocompatible agent composition that includes biocompatible agent and one or more photoreactive groups; and treating the collagenous tissue scaffold and biocompatible agent composition to activate the photoreactive groups and bond the biocompatible agent to the tissue scaffold via one or more activated photoreactive groups. Implantable prostheses formed of the tissue graft material are also contemplated.
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Page/Page column 16
(2010/11/30)
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- Coatings including natural biodegradable polysaccharides and uses thereof
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Biodegradable coatings and articles that include natural biodegradable polysaccharides are described. The coatings and articles are formed from a plurality of natural biodegradable polysaccharides having pendent coupling groups.
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- Design and synthesis of site directed maleimide bifunctional chelators for technetium and rhenium
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A new family of heterobifunctional linkers (L1-L9) containing a terminus consisting of a tridentate donor set for coordination of the {M(CO) 3}+ core (M = Tc, Re), and a thiol reactive maleimide group has been prepared conveniently and in high yield under Mitsunobu reaction conditions by the coupling of an appropriate alcohol derivative with maleimide. The rhenium complexes [Re(CO)3(Lx)]Br (x = 1-9) were prepared in good yields from the reactions of the ligands and (NEt4) 2[Re(CO)3Br3] in refluxing methanol. The ligands and their Re complexes were characterized by 1H and 13C NMR, IR, and ESI-MS. Ligand L4 and [Re(CO)3(L5)]Br have been structurally characterized by X-ray crystallography. Photoexcitation of solutions of the complexes [Re(CO)3(Lx)]Br (x = 4-6) gives rise to intense and prolonged luminescence at room temperature (fluorescence lifetimes of ca. 16 μs). The ligands and their Re complexes react smoothly at the maleimide linker with sulfhydryl groups of peptides and proteins at room temperature in phosphate-buffered saline (PBS, pH 7.4) to form stable thioether bioconjugates. The photoluminescence properties of the labeled conjugates are similar to those of the parent complexes, but with even longer lifetimes. The ligands can also be labeled at room temperature with 99mTc to give chemically robust complexes. The corresponding hydrazinonicotinamide derivative N-[5-(6′-hydrazinopyridine-3′-carbonyl)aminopentyl]-maleimide (L10) was also prepared. While coupling of L10 to cysteine ethylester and synthesis of the rhenium derivative [ReCl3(HYNIC-maleimide)2] were successfully accomplished, attempts to couple [ReCl3(HYNIC-maleimide) 2] to glutathione or BSA yielded intractable mixtures. The Royal Society of Chemistry 2005.
- Banerjee, Sangeeta Ray,Schaffer, Paul,Babich, John W.,Valliant, John F.,Zubieta, Jon
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p. 3886 - 3897
(2007/10/03)
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- MALEIMIDE RESIN WITH CYANURATE CORE
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Isocyanurate compounds or resins have the structure (I) in which Y is an hydroxyl group -OH or a maleimide group Formula (II) provided that at least one maleimide group is present, and Q is any divalent organic moiety, aliphatic or aromatic.
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Page/Page column 11
(2008/06/13)
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- Curable compositions containing thiazole functionality
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Adhesion promoting compounds or resins containing a thiazole functionality (including benzothiazole) and a polymerizable functionality (Z) give improved adhesive strength to metal substrates. A representative structure is the following, in which R1 and R2 together can form a cyclic or aromatic structure, or are linear or branched organic moieties.
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- NEW EFFECTOR CONJUGATES, PROCESS FOR THEIR PRODUCTION AND THEIR PHARMACEUTICAL USE
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Conjugates of epothilones and epothilone derivatives (as effectors) with suitable biomolecules (as recognition units) are described. Their production is carried out by the effectors being reacted with suitable linkers, and the compounds that are produced are conjugated to the recognition units. The pharmaceutical use of the conjugates for treating proliferative or angiogenesis-associated processes is described.
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Page/Page column 46
(2010/02/06)
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- Compositions and methods for enhancing drug delivery across and into epithelial tissues
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This invention provides compositions and methods for enhancing delivery of drugs and other agents across epithelial tissues, including the skin, gastrointestinal tract, pulmonary epithelium, ocular tissues and the like. The compositions and methods are also useful for delivery across endothelial tissues, including the blood brain barrier. The compositions and methods employ a delivery enhancing transporter that has sufficient guanidino or amidino sidechain moieties to enhance delivery of a compound conjugated to the reagent across one or more layers of the tissue, compared to the non-conjugated compound. The delivery-enhancing polymers include, for example, poly-arginine molecules that are preferably between about 6 and 25 residues in length.
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Drawing sheet 23
(2010/02/07)
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- Design, synthesis, and biochemical evaluation of N-substituted maleimides as inhibitors of prostaglandin endoperoxide synthases
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N-(Carboxyalkyl)maleimides are rapid as well as time-dependent inhibitors of prostaglandin endoperoxide synthase (PGHS). The corresponding N- alkylmaleimides were only time-dependent inactivators of PGHS, suggesting that the carboxylate is critical for rapid inhibition. Several N-substituted maleimide analogs containing structural features similar to those of the nonsteroidal anti-inflammatory drug aspirin were synthesized and evaluated as inhibitors of PGHS. Most of the aspirin-like maleimides inactivated the cyclooxygenase activity of purified ovine PGHS-1 in a time- and concentration-dependent manner similar to that of aspirin. The peroxidase activity of PGHS was also inactivated by the maleimide analogs. The cyclooxygenase activity of the inducible isozyme, i.e., PGHS-2, was also inhibited by these compounds. The corresponding succinimide analog of N-5- maleimido-2-acetoxy-1-benzoic acid did not inhibit either enzyme activity, suggesting that inactivation was due to covalent modification of the protein. The mechanism of inhibition of PGHS-1 by N-(carboxyheptyl)maleimide was investigated. Incubation of apoPGHS-1 with 2 equiv of N-(carboxyheptyl)[3,4- 14C]maleimide led to the incorporation of radioactivity in the protein, but no adduct was detected by reversed-phase HPLC, suggesting that it was unstable to the chromatographic conditions. Furthermore, hematin- reconstituted PGHS-1, which was rapidly inhibited by N- (carboxyheptyl)maleimide, displayed spontaneous regeneration of about 50% of the cyclooxygenase and peroxidase activities, suggesting that the adduct responsible for the inhibition breaks down to regenerate active enzyme. ApoPGHS-1, inhibited by N-(carboxyheptyl)maleimide, did not display regeneration of enzyme activity, but addition of hematin to the inhibited apoenzyme led to spontaneous recovery of about 50% of cyclooxygenase activity. These results suggest that addition of heme leads to a conformational change in the protein which increases the susceptibility of the adduct toward hydrolytic cleavage. ApoPGHS-1, pretreated with N(carboxyheptyl)maleimide, was resistant to trypsin cleavage, suggesting that the carboxylate functionality of the maleimide binds in the cyclooxygenase channel. A model for the interaction of N-(carboxyheptyl)maleimide in the cyclooxygenase active site is proposed.
- Kalgutkar, Amit S.,Crews, Brenda C.,Marnett, Lawrence J.
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p. 1692 - 1703
(2007/10/03)
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- Synthesis of heterobifunctional crosslinking reagents: ω-(N-Maleimido)-alkanoic acid hydrazides
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ω-(N-Maleimido)alkanoic acid hydrazides (6a-c) with C11, C7 and C5 alkyl arms have been synthesized by novel method. The method involves the reaction between maleic anhydride and ω-aminoalkanoic acids (2) to get maleamic acids (3) which are in turn cyclized to ω-(N-maleimido)alkanoic acids (4) using fused sodium acetate and acetic anhydride. These maleimidoalkanoic acids are activated and then converted in situ into their N-2-t-butyloxycarbonyl hydrazides (5) from which the t-butyl-based protecting group is cleaved without damage to the maleimide molety to obtain the title compounds.
- Ambekar, Sarvottam Y.,Gowda, D. Channe
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p. 184 - 186
(2007/10/03)
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- Method for preparing thioether conjugates
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A method is provided for preparing thioether conjugates useful in treating neoplastic diseases and preferably formed of the BR96 immunoconjugate synthesized from a heterobifunctional linker of doxorubicin, wherein a purified and reduced form of BR96 MAb is conjugated with the 6-maleimidocaproyl hydrazone of doxorubicin and the resulting crude conjugate is purified.
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