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Antibody drug conjugation

Hélène Kaplon, Janice M Reichert
For the past 10 years, the annual 'Antibodies to watch' articles have provided updates on key events in the late-stage development of antibody therapeutics, such as first regulatory review or approval, that occurred in the year before publication or were anticipated to occur during the year of publication. To commemorate the 10th anniversary of the article series and to celebrate the 2018 Nobel Prizes in Chemistry and in Physiology or Medicine, which were given for work that is highly relevant to antibody therapeutics research and development, we expanded the scope of the data presented to include an overview of all commercial clinical development of antibody therapeutics and approval success rates for this class of molecules...
December 5, 2018: MAbs
Gunter von Minckwitz, Chiun-Sheng Huang, Max S Mano, Sibylle Loibl, Eleftherios P Mamounas, Michael Untch, Norman Wolmark, Priya Rastogi, Andreas Schneeweiss, Andres Redondo, Hans H Fischer, William Jacot, Alison K Conlin, Claudia Arce-Salinas, Irene L Wapnir, Christian Jackisch, Michael P DiGiovanna, Peter A Fasching, John P Crown, Pia Wülfing, Zhimin Shao, Elena Rota Caremoli, Haiyan Wu, Lisa H Lam, David Tesarowski, Melanie Smitt, Hannah Douthwaite, Stina M Singel, Charles E Geyer
BACKGROUND: Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy...
December 5, 2018: New England Journal of Medicine
Sarah Davies, Benjamin J Stenton, Gonçalo J L Bernardes
Bioorthogonal decaging reactions are highly selective transformations which involve the cleavage of a protecting group from a molecule of interest. Decaging reactions can be classified into subgroups depending on the nature of the trigger; they can be photo-, metal- or small molecule-triggered. Due to their highly selective and biocompatible nature, they can be carried out in living systems as they do not interfere with any endogenous processes. This gain-of-function allows controlled activation of proteins and release of fluorophores and drugs in vivo ...
November 30, 2018: Chimia
Mark L Zangardi, Laura M Spring, Aiko Nagayama, Aditya Bardia
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that disproportionately impacts younger women and is associated with a poor prognosis. Systemic treatment options for metastatic TNBC (mTNBC) are limited to successive lines of cytotoxic chemotherapy agents with low response rates. Trop-2 has been identified as a potential target in epithelial cancers such as TNBC; this has encouraged the development of sacituzumab govitecan (IMMU-132), an anti-Trop-2 antibody-drug conjugate (ADC)...
December 3, 2018: Expert Opinion on Investigational Drugs
Elizabeth Love, Afrah Sattikar, Hannah Cook, Kevin Gillen, Jonathan M Large, Seema Patel, David Matthews, Andy Merritt
Antibody-drug conjugates (ADCs) are a growing class of therapeutics, harnessing the specificity of antibodies and the cell-killing potency of small molecule drugs. Beyond cytotoxics, there are few examples of the application of an ADC approach to difficult drug discovery targets. Here, we present the initial development of a non-internalising ADC, with a view to achieving selective inhibition of an extracellular protein. Employing the well investigated matrix metalloproteinase-9 (MMP-9) as our model, we adapt a broad-spectrum, non-selective MMP inhibitor for conjugation and link this to a targeting MMP-9 antibody...
December 3, 2018: Chembiochem: a European Journal of Chemical Biology
Tania Jain, Mark R Litzow
Therapeutic options for acute lymphoblastic leukemia, especially in the relapsed/refractory setting, have expanded significantly in recent times. However, this comes at the cost of toxicities: medical as well as financial. We highlight some of the unique toxicities associated with the novel agents to apprise our readers about what to expect, how to recognize them, and how to manage these toxicities. One of the toxicities seen with inotuzumab, a CD22 antibody drug conjugate, is sinusoidal obstruction syndrome, which can be fatal in >80% of patients if associated with multiorgan failure...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
Shira Dinner, Michaela Liedtke
The use of multiagent combination chemotherapy regimens results in cure rates of >90% for children and ∼40% for adults with acute lymphoblastic leukemia (ALL) but is associated with extensive toxicity and disappointingly low efficacy in relapsed patients. ALL blast cells express several surface antigens, including CD20, CD22, and CD19, which represent valuable targets for immunotherapy. Monoclonal antibodies, antibody-drug conjugates, and bispecific T-cell-engaging antibodies targeting these antigens offer novel mechanisms of action...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
Kuo-Yang Huang, Ruei-Min Chen, Hsin-Chung Lin, Wei-Hung Cheng, Hsin-An Lin, Wei-Ning Lin, Po-Jung Huang, Cheng-Hsun Chiu, Petrus Tang
BACKGROUND: Autophagy has been shown to be involved in the pathogenesis of several protists, offering prospects for the developments of new drugs targeting autophagy. However, there is no evidence illustrating functional autophagy in the deep-branching trichomonads. The human parasitic protist Trichomonas vaginalis has been predicted to possess reduced autophagic machinery, with only autophagy-related protein 8 (Atg8) conjugation system required for autophagosome formation. METHODS: The recombinant protein of TvAtg8 (rTvAtg8) and the polyclonal antibody against rTvAtg8 were generated...
November 22, 2018: Journal of Microbiology, Immunology, and Infection, Wei Mian Yu Gan Ran za Zhi
Yuwei Tian, Jennifer L Lippens, Chawita Netirojjanakul, Iain Campuzano, Brandon T Ruotolo
Antibody-drug conjugates (ADCs) are antibody-based therapeutics that have proven to be highly effective cancer treatment platforms. They are comprised of monoclonal antibodies conjugated with highly potent drugs via chemical linkers. Compared to cysteine-targeted chemistries, conjugation at native lysine residues can lead to a higher degree of structural heterogeneity, and thus it is important to evaluate the impact of conjugation on antibody conformation. Here, we present a workflow involving native ion mobility (IM)-MS and gas-phase unfolding for the structural characterization of lysine-linked mAb-biotin conjugates...
November 30, 2018: Protein Science: a Publication of the Protein Society
Vijayalaxmi Gupta, Sneha Bhavanasi, Mohiuddin Quadir, Kevin Singh, Gaurav Ghosh, Kritin Vasamreddy, Arnab Ghosh, Teruna J Siahaan, Snigdha Banerjee, Sushanta K Banerjee
PEGylation is a biochemical modification process of bioactive molecules with polyethylene glycol (PEG), which lends several desirable properties to proteins/peptides, antibodies, and vesicles considered to be used for therapy or genetic modification of cells. However, PEGylation of proteins is a complex process and can be carried out using more than one strategy that depends on the nature of the protein and the desired application. Proteins of interest are covalently conjugated or non-covalently complexed with inert PEG strings...
November 29, 2018: Journal of Cell Communication and Signaling
Baharak Bahmani, Mayuko Uehara, Farideh Ordikhani, Xiaofei Li, Liwei Jiang, Naima Banouni, Takaharu Ichimura, Vivek Kasinath, Siawosh K Eskandari, Nasim Annabi, Jonathan S Bromberg, Leonard D Shultz, Dale L Greiner, Reza Abdi
BACKGROUND: Nanomedicine offers an excellent opportunity to tackle treatment-refractory malignancies by enhancing the delivery of therapeutics to the tumor site. High endothelial venules (HEVs) are found primarily in lymph nodes or formed de novo in peripheral tissues during inflammatory responses. They express peripheral node addressin (PNAd), which is recognized by the monoclonal antibody MECA79. METHODS: Here, we demonstrated that HEVs form de novo in human pancreatic ductal adenocarcinoma (PDAC)...
November 26, 2018: EBioMedicine
Candy S Hwang, Beverly Ellis, Bin Zhou, Kim D Janda
Heroin is a highly abused opioid that has reached epidemic status within the United States. Yet, existing therapies to treat addiction are inadequate and frequently result into rates of high recidivism. Vaccination against heroin offers a promising alternative therapeutic option but requires further development to enhance the vaccine's performance. Hsp70 is a conserved protein with known immunomodulatory properties and is considered an excellent immunodominant antigen. Within an antidrug vaccine context, we envisioned Hsp70 as a potential dual carrier-adjuvant, wherein immunogenicity would be increased by co-localization of adjuvant and antigenic drug hapten...
November 20, 2018: Bioorganic & Medicinal Chemistry
Mark Timms, Katherine Ganio, Grace Forbes, Simon Bailey, Rohan Steel
CJC-1295 is a 30 amino acid peptide-based drug that stimulates the release of growth hormone (GH) from the pituitary gland. It is unique among performance enhancing peptides due to the presence of a reactive maleimidopropionic acid group that covalently links the peptide to free thiols on the surface of plasma proteins. Once conjugated, CJC-1295 remains active in the bloodstream for significantly longer than non-conjugated peptide-based drugs that are rapidly excreted. Conjugation of CJC-1295 to plasma proteins prevents its detection by top-down mass spectrometry based peptide screening protocols as it effectively becomes a macromolecular protein with an undefined molecular weight...
November 29, 2018: Drug Testing and Analysis
Robert Pola, Vlastimil Král, Sergey K Filippov, Leonid Kaberov, Tomáš Etrych, Irena Sieglova, Juraj Sedlacek, Milan Fábry, Michal Pechar
A water-soluble polymer cancerostatic actively targeted against cancer cells expressing a disialoganglioside antigen GD2 was designed, synthesized and characterized. A polymer conjugate of an anti-tumor drug doxorubicin with a N-(2-hydroxypropyl)methacrylamide-based copolymer was specifically targeted against GD2 antigen-positive tumor cells using a recombinant single chain fragment (scFv) of an anti-GD2 monoclonal antibody. The targeting protein ligand was attached to the polymer-drug conjugate either via a covalent bond between the amino groups of the protein using a traditional non-specific aminolytic reaction with a reactive polymer precursor or via a non-covalent but highly specific interaction between bungarotoxin covalently linked to the polymer and the recombinant scFv modified with a C-terminal bungarotoxin-binding peptide...
November 28, 2018: Biomacromolecules
Tania Jain, Mark R Litzow
Therapeutic options for acute lymphoblastic leukemia, especially in the relapsed/refractory setting, have expanded significantly in recent times. However, this comes at the cost of toxicities: medical as well as financial. We highlight some of the unique toxicities associated with the novel agents to apprise our readers about what to expect, how to recognize them, and how to manage these toxicities. One of the toxicities seen with inotuzumab, a CD22 antibody drug conjugate, is sinusoidal obstruction syndrome, which can be fatal in >80% of patients if associated with multiorgan failure...
November 27, 2018: Blood Advances
Jianqin Lu, Xiangsheng Liu, Yu-Pei Liao, Xiang Wang, Ayman Ahmed, Wen Jiang, Ying Ji, Huan Meng, Andre E Nel
Immunotherapy provides the best approach to reduce the high mortality of metastatic breast cancer (BC). We demonstrate a chemo-immunotherapy approach, which utilizes a liposomal carrier to simultaneously trigger immunogenic cell death (ICD) as well as interfere in the regionally overexpressed immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO-1) at the BC tumor site. The liposome was constructed by self-assembly of a phospholipid-conjugated prodrug, indoximod (IND), which inhibits the IDO-1 pathway, followed by the remote loading of the ICD-inducing chemo drug, doxorubicin (DOX)...
November 27, 2018: ACS Nano
Xiao-Ge Liu, Shuai Lu, Dong-Qun Liu, Lun Zhang, Ling-Xiao Zhang, Xiao-Lin Yu, Rui-Tian Liu
It is widely accepted that amyloid oligomers are the most toxic species to initiate the pathologic processes of Parkinson's disease (PD) and Huntingdon's disease (HD). But there is no definitive diagnosis for PD and HD at their early stages. Here, we conjugated an amyloid oligomer-specific scFv antibody (W20) to PEGylated superparamagnetic iron oxide nanoparticles (SPIONs) and detected the properties of the SPIONs conjugated with W20. The results showed that W20-SPIONs, with the size of around 11.8 nm in diameter, were stable and nontoxic, and had enough relaxation capacity to be used as an MRI contrast agent...
November 24, 2018: Brain Research
Daniel Y Lee, Kwang Suk Lim, Gabriel M Valencia, Minjin Jung, David A Bull, Young-Wook Won
Conventional combinatorial anticancer therapy has shown promising outcomes; still, a significant interest in developing new methods to reinforce and possibly merge chemotherapy and immunotherapy persists. Here, a new one-step method that immediately modifies immune cells into a targeted form of chemoimmunotherapy through spontaneous and rapid incorporation of hydrophobized antibody-drug conjugates (ADCs) on the surface of immune cells is presented. Therapeutic objectives of this approach include targeted delivery of a potent chemotherapeutic agent to avoid adverse effects, enhancing the mobilization of infused immune cells toward tumor sites, and preserving the intense cytotoxic activities of immune cells against tumor cells...
November 2018: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
Meghdad Abdollahpour-Alitappeh, Majid Lotfinia, Tohid Gharibi, Jalal Mardaneh, Behrouz Farhadihosseinabadi, Pegah Larki, Babak Faghfourian, Koushan Sineh Sepehr, Kazem Abbaszadeh-Goudarzi, Ghasem Abbaszadeh-Goudarzi, Behrooz Johari, Mohammad Reza Zali, Nader Bagheri
Targeted delivery of therapeutic molecules into cancer cells is considered as a promising strategy to tackle cancer. Antibody-drug conjugates (ADCs), in which a monoclonal antibody (mAb) is conjugated to biologically active drugs through chemical linkers, have emerged as a promising class of anticancer treatment agents, being one of the fastest growing fields in cancer therapy. The failure of early ADCs led researchers to explore strategies to develop more effective and improved ADCs with lower levels of unconjugated mAbs and more-stable linkers between the drug and the antibody, which show improved pharmacokinetic properties, therapeutic indexes, and safety profiles...
November 27, 2018: Journal of Cellular Physiology
Puneet Tyagi, Sergei Pechenov, Jonathan RiosDoria, Luke Masterson, Niall J Dickinson, Philip Howard, Shenlan Mao, Jay Harper, Leslie Wetzel, Kwok Yo, J Anand Subramony
We describe the development and evaluation of pyrrolobenzodiazepines (PBDs) in poly(DL-lactide-co-glycolide) (PLGA) and lipid (LNP) nanoparticle drug delivery systems. We have established that the partition coefficient (LogP) of PBD is a key influencer of the encapsulation efficiency in nanoparticle systems, with higher LogP values associated with higher encapsulation efficiencies toward increased drug payload delivery and better antitumor efficacy. Cytotoxicity assays demonstrated that compounds with higher LogP values demonstrated higher 50% inhibitory concentration values than the free drug...
November 22, 2018: Journal of Pharmaceutical Sciences
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