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Antibody drug conjugates

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https://www.readbyqxmd.com/read/28801661/statistical-characterization-of-therapeutic-protein-modifications
#1
Tsung-Heng Tsai, Zhiqi Hao, Qiuting Hong, Benjamin Moore, Cinzia Stella, Jeffrey H Zhang, Yan Chen, Michael Kim, Theo Koulis, Gregory A Ryslik, Erik Verschueren, Fred Jacobson, William E Haskins, Olga Vitek
Peptide mapping with liquid chromatography-tandem mass spectrometry (LC-MS/MS) is an important analytical method for characterization of post-translational and chemical modifications in therapeutic proteins. Despite its importance, there is currently no consensus on the statistical analysis of the resulting data. In this manuscript, we distinguish three statistical goals for therapeutic protein characterization: (1) estimation of site occupancy of modifications in one condition, (2) detection of differential site occupancy between conditions, and (3) estimation of combined site occupancy across multiple modification sites...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28798339/real-time-analysis-on-drug-antibody-ratio-of-antibody-drug-conjugates-for-synthesis-process-optimization-and-quality-control
#2
Yubo Tang, Feng Tang, Yang Yang, Lei Zhao, Hu Zhou, Jinhua Dong, Wei Huang
Drug-antibody ratio (DAR) of antibody-drug conjugates (ADCs) is important for their therapeutic efficacy and pharmacokinetics, therefore control on DAR in synthesis process is a key for ADC quality control. Although various analytical methods were reported, the real-time monitoring on DAR is still a challenge because time-consuming sample preparation is usually needed during the analysis. Antibody deglycosylation of ADC simplifies DAR measurement, however long-time PNGaseF digestion for deglycosylation hampers the real-time detection...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28792782/emerging-antibody-drug-conjugates-for-treating-lymphoid-malignancies
#3
Anna Wolska-Washer, Pawel Robak, Piotr Smolewski, Tadeusz Robak
Antibody-drug conjugates (ADC) are monoclonal antibodies (Mabs) attached to biologically active drugs through specialized chemical linkers. They deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. These agents should improve the potency of chemotherapy by increasing the accumulation of the cytotoxic drug within or near the neoplastic cells with reduced systemic effects. Areas covered and methods: A literature review was conducted using the MEDLINE database, PubMed, for articles in English examining Mabs, B-cell receptor pathway inhibitors and immunomodulating drugs...
August 9, 2017: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/28791656/egfr-as-a-target-for-glioblastoma-treatment-an-unfulfilled-promise
#4
Manfred Westphal, Cecile L Maire, Katrin Lamszus
The receptor for epidermal growth factor (EGFR) is a prime target for cancer therapy across a broad variety of tumor types. As it is a tyrosine kinase, small molecule tyrosine kinase inhibitors (TKIs) targeting signal transduction, as well as monoclonal antibodies against the EGFR, have been investigated as anti-tumor agents. However, despite the long-known enigmatic EGFR gene amplification and protein overexpression in glioblastoma, the most aggressive intrinsic human brain tumor, the potential of EGFR as a target for this tumor type has been unfulfilled...
August 8, 2017: CNS Drugs
https://www.readbyqxmd.com/read/28776425/treatment-of-adult-acute-lymphoblastic-leukemia-with-inotuzumab-ozogamicin
#5
Shilpa Paul, Caitlin R Rausch, Hagop Kantarjian, Elias J Jabbour
Treatment of adult acute lymphoblastic leukemia (ALL) has largely relied on cytotoxic chemotherapy agents borrowed from successful treatment regimens of pediatric ALL. However, the high cure rates seen in pediatric ALL have not been replicated in adults. In recent years, the development of monoclonal antibodies targeting cell surface antigens, such as CD19 and CD20, have significantly improved outcomes when used alone or in combination with cytotoxic chemotherapy. With these novel agents come challenges in managing adverse events, understanding mechanisms of resistance and determining their optimal place in therapy alongside conventional chemotherapy and allogeneic stem cell transplant...
August 4, 2017: Future Oncology
https://www.readbyqxmd.com/read/28771632/refinement-of-immunizing-antigens-to-produce-functional-blocking-antibodies-against-the-ania-nitrite-reductase-of-neisseria-gonorrhoeae
#6
Lucy K Shewell, Freda E-C Jen, Michael P Jennings
The emergence of multi-drug resistant Neisseria gonorrhoeae has generated an urgent need for novel therapies or a vaccine to prevent gonococcal disease. In this study we investigate the potential of targeting the surface exposed nitrite reductase, AniA, to block activity by producing functional blocking antibodies. AniA activity is essential for anaerobic growth and biofilm formation of N. gonorrhoeae and functional blocking antibodies may prevent colonisation and disease. Seven peptides covering regions adjacent to the active site were designed based on the AniA structure...
2017: PloS One
https://www.readbyqxmd.com/read/28763236/hinge-deficient-igg1-fc-fusion-application-to-human-lactoferrin
#7
Yuki Shiga, Daisuke Murata, Akinori Sugimoto, Yuta Oshima, Minoru Tada, Akiko Ishii-Watabe, Kenichiro Imai, Kentaro Tomii, Takashi Takeuchi, Shinji Kagaya, Atsushi Sato
Fusion of therapeutic proteins with an antibody Fc domain is a strategy applied widely to increase their plasma half-life. Previously, we reported a recombinant human lactoferrin (hLF)-immunoglobulin G1 Fc fusion protein (hLF-hinge-CH2-CH3) with enhanced pharmacokinetic properties [Shiga, Y. et al., Eur J Pharm Sci., 2015, 67, 136-143.]. This conventional Fc fusion protein, however, has the potential drawback of inducing undesirable Fc-mediated immune effector functions (antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity)...
August 1, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28763044/tubulin-inhibitor-based-antibody-drug-conjugates-for-cancer-therapy
#8
REVIEW
Hao Chen, Zongtao Lin, Kinsie E Arnst, Duane D Miller, Wei Li
Antibody-drug conjugates (ADCs) are a class of highly potent biopharmaceutical drugs generated by conjugating cytotoxic drugs with specific monoclonal antibodies through appropriate linkers. Specific antibodies used to guide potent warheads to tumor tissues can effectively reduce undesired side effects of the cytotoxic drugs. An in-depth understanding of antibodies, linkers, conjugation strategies, cytotoxic drugs, and their molecular targets has led to the successful development of several approved ADCs. These ADCs are powerful therapeutics for cancer treatment, enabling wider therapeutic windows, improved pharmacokinetic/pharmacodynamic properties, and enhanced efficacy...
August 1, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28762384/her2-positive-breast-cancer-is-lost-in-translation-time-for-patient-centered-research
#9
REVIEW
Isabelle Gingras, Géraldine Gebhart, Evandro de Azambuja, Martine Piccart-Gebhart
No biomarker beyond HER2 itself, which suffers from a low positive predictive value, has demonstrated clinical utility in breast cancer, despite numerous attempts to improve treatment tailoring for the growing number of anti-HER2 targeted therapies. This prompted us to examine the body of evidence, using a systematic approach, to identify putative predictive biomarkers in HER2-positive breast cancer, and discuss the hitherto failure to address the needs of patients. In the future, it is hoped immune-based biomarkers will predict benefit from anti-HER2 treatments in the neoadjuvant and adjuvant settings...
August 1, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28760499/nanoparticles-and-targeted-drug-delivery-in-cancer-therapy
#10
REVIEW
Behdokht Bahrami, Mohammad Hojjat-Farsangi, Hamed Mohammadi, Enayat Anvari, Ghasem Ghalamfarsa, Mehdi Yousefi, Farhad Jadidi-Niaragh
Surgery, chemotherapy, radiotherapy, and hormone therapy are the main common anti-tumor therapeutic approaches. However, the non-specific targeting of cancer cells has made these approaches non-effective in the significant number of patients. Non-specific targeting of malignant cells also makes indispensable the application of the higher doses of drugs to reach the tumor region. Therefore, there are two main barriers in the way to reach the tumor area with maximum efficacy. The first, inhibition of drug delivery to healthy non-cancer cells and the second, the direct conduction of drugs into tumor site...
July 29, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28758366/pyrrolysine-amber-stop-codon-suppression-development-and-applications
#11
Robin Brabham, Martin Anthony Fascione
The pyrrolysine tRNA synthetase-tRNA pair is likely one of the most promiscuous tRNA-synthetase pairs found in nature, capable of genetically encoding a plethora of non-canonical amino acids through stop codon reassignment. Proteins containing reactive handles, post-translational modification mimics or both can be produced in practical quantities, allowing inter alia the probing of biological pathways, the generation of antibody-drug conjugates, and enhancing protein function. This Minireview summarises the development of pyrrolysine amber stop codon suppression, presents some of the considerations required to utilise this technique to its greatest potential, and showcases the creative ways in which this technique has led to a better understanding of biological systems...
July 30, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28757155/antibody-drug-conjugates-for-treatment-of-breast-cancer-novel-targets-and-diverse-approaches-in-adc-design
#12
REVIEW
Pamela A Trail, Gene M Dubowchik, Timothy Lowinger
Breast cancer is a heterogeneous group of malignancies with a spectrum of molecular subtypes, pathologies and outcomes that together comprise the most common non-cutaneous cancer in women. Currently, over 80% of breast cancer patients are diagnosed at relatively early stages of disease where there are encouraging data on outcomes and long term survival. However, there is currently no curative option for those patients with metastatic disease and there is a substantial medical need to identify effective and safe treatment options for these patients...
July 27, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28757080/a-fusion-receptor-as-a-safety-switch-detection-and-purification-biomarker-for-adoptive-transferred-t-cells
#13
Xiuqi Wu, Bizhi Shi, Jiqin Zhang, Zhimin Shi, Shengmeng Di, Minliang Fan, Huiping Gao, Hai Wang, Jianren Gu, Hua Jiang, Zonghai Li
The incorporation of an endogenous safety switch represents a rational strategy for the control of toxicities following the administration of adoptive T cell therapies. An ideal safety switch should be capable of depleting the transferred T cells with minimal injury to normal tissues. We generated a fusion receptor by engineering a cryptic 806 epitope of human epidermal growth factor receptor (EGFR) into the N terminus of the full-length human folate receptor 1 (FOLR1), designated as FR806. The expression of FR806 allows transduced T cells to be targeted with CH12, a monoclonal antibody recognizing the 806 epitope, but not wild-type EGFR in healthy tissues...
July 3, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28756350/immunotherapy-in-adult-acute-leukemia
#14
REVIEW
Sabine Blum, Filipe Martins, Michael Lübbert
The treatment of acute myeloid leukemia (AML) did not evolve profoundly in the last decades. Some improvement has been made for acute lymphoblastic leukemia (ALL). Emerging new treatment modalities, such as immunotherapy, are now beginning to be available for acute leukemia, mostly for patients suffering from ALL. This review aims to give an overview of these new therapeutic approaches, especially those already available. The focus is on cell-based immunotherapy, or molecules using preexisting host cells. Underlying mechanisms are explained and an overview of clinical experience with phase 1-3 studies is given...
June 29, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28754863/pathological-expression-of-tissue-factor-confers-promising-antitumor-response-to-a-novel-therapeutic-antibody-sc1-in-triple-negative-breast-cancer-and-pancreatic-adenocarcinoma
#15
Xuesai Zhang, Qingrou Li, Hui Zhao, Lanping Ma, Tao Meng, Jianchang Qian, Rui Jin, Jingkang Shen, Ker Yu
The pathological presence of tissue factor (TF) in cancer cells promotes tumor-initiated thrombosis and cancer metastasis. We found that TF is aberrantly present in large percentage of aggressive triple negative breast cancer (TNBC) and pancreatic adenocarcinoma (PaC), two most lethal forms of malignancy that urgently need effective treatment. TF expression in TNBC clustered with higher levels of vimentin, basal-type keratins KRT5/14 and caveolin-1 but lower levels of luminal-type biomarkers. We developed a novel and specific anti-TF therapeutic antibody SC1, which displayed an exceedingly high potency against TF extracellular domain (EC50: 0...
July 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28753442/the-antitumor-activity-of-imgn529-a-cd37-targeting-antibody-drug-conjugate-is-potentiated-by-rituximab-in-non-hodgkin-lymphoma-models
#16
Stuart W Hicks, Katharine C Lai, L Cristina Gavrilescu, Yong Yi, Surina Sikka, Prerak Shah, Meghan E Kelly, Jenny Lee, Leanne Lanieri, Jose F Ponte, Callum M Sloss, Angela Romanelli
Naratuximab emtansine (IMGN529) is an investigational antibody-drug conjugate consisting of a CD37-targeting antibody conjugated to the maytansine-derived microtuble disruptor, DM1. IMGN529 has shown promising preclinical and clinical activity in non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). Due to the aggressive nature of the disease, DLBCL is often treated with combination therapies to maximize clinical outcomes; therefore, we investigated the potential of combining IMGN529 with both standard-of-care and emerging therapies against multiple oncology-relevant targets and pathways...
July 25, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28752254/interaction-between-c18-fatty-acids-and-dope-peg2000-in-langmuir-monolayers-effect-of-degree-of-unsaturation
#17
Lai Ti Gew, Misni Misran
In this study, we address the effect of the cis-double bond in 1,2-dioleoyl-sn-glycero-3-phosphoethanolamide-N-[methoxy(polyethylene glycol)-2000, DOPE PEG2000 (DP), on the Langmuir monolayer of C18 fatty acids-namely, stearic acid (SA), oleic acid (L1), linoleic acid (L2), and linolenic acid (L3)-with the same head group but different degrees of saturation on their hydrocarbon chains. Negative values of Gibbs free energy of mixing (ΔG mix) were obtained throughout the investigated ranges of the unsaturated C18 fatty-acid (L1, L2 and L3) mixed systems, indicating that very strong attractions occurred between molecules in the monolayers...
July 27, 2017: Journal of Biological Physics
https://www.readbyqxmd.com/read/28751378/discovery-of-a-microbial-transglutaminase-enabling-highly-site-specific-labeling-of-proteins
#18
Wojtek Steffen, Fu Chong Ko, Jigar Patel, Victor Lyamichev, Tom Albert, Jörg Benz, Markus G Rudolph, Frank Bergmann, Thomas Streidl, Peter Kratzsch, Mara Boenitz-Dulat, Tobias Oelschlaegel, Michael Schraeml
Microbial transglutaminases (MTGs) catalyze the formation of Gln-Lys isopeptide bonds and are widely used for the crosslinking of proteins and peptides in food and biotechnological applications, for example, to improve the texture of protein-rich foods or in generating antibody-drug conjugates. Currently used MTGs have low substrate specificity, impeding their biotechnological use as enzymes that don't cross-react with nontarget substrates (i.e. as bio-orthogonal labeling systems). Here, we report the discovery of a MTG from Kutzneria albida (KalbTG) which exhibited no cross-reactivity with known MTG substrates or commonly used target proteins such as antibodies...
July 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28751189/targeted-therapies-in-hematological-malignancies-using-therapeutic-monoclonal-antibodies-against-eph-family-receptors
#19
REVIEW
Sara Charmsaz, Andrew M Scott, Andrew W Boyd
The use of monoclonal antibodies and molecules derived from them has achieved considerable attention and success in recent years establishing this mode of therapy as important therapeutic strategy in many cancers and in particular in hematological tumors. Monoclonal antibodies recognize cell surface antigens expressed on target cells and mediate their function through various mechanisms, such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity or by modulating the immune system. The efficacy of monoclonal antibody therapy can be improved when conjugates to a highly potent payloads including cytotoxic drugs and radiolabelled isotopes...
July 24, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28749929/chemoenzymatic-synthesis-of-glycoengineered-igg-antibodies-and-glycosite-specific-antibody-drug-conjugates
#20
Feng Tang, Lai-Xi Wang, Wei Huang
Glycoengineered therapeutic antibodies and glycosite-specific antibody-drug conjugates (gsADCs) have generated great interest among researchers because of their therapeutic potential. Endoglycosidase-catalyzed in vitro glycoengineering technology is a powerful tool for IgG Fc (fragment cystallizable) N-glycosylation remodeling. In this protocol, native heterogeneously glycosylated IgG N-glycans are first deglycosylated with a wild-type endoglycosidase. Next, a homogeneous N-glycan substrate, presynthesized as described here, is attached to the remaining N-acetylglucosamine (GlcNAc) of IgG, using a mutant endoglycosidase (also called endoglycosynthase) that lacks hydrolytic activity but possesses transglycosylation activity for glycoengineering...
August 2017: Nature Protocols
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