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Antibody-Drug Conjugate

Jitendrakumar Patel, Jitendra Amrutiya, Priyanka Bhatt, Ankit Javia, Mukul Jain, Ambikanandan Misra
Aim of this study was to develop anti EGFR antibody conjugated poly (lactide-co-glycolide) nanoparticles (NPs) to target epidermal growth factor receptor, highly expressed on non-small cell lung cancer cells to improve cytotoxicity and site specificity. Cetuximab was conjugated to Docetaxel loaded PLGA NPs by known EDC/NHS chemistry and characterized for size, zeta potential, conjugation efficiency and results were 128.4 ±3.6 nm, -31.0 ± 0.8 mV and 39.77 ± 3.4% respectively. In-vitro release study demonstrated sustained release of drug from NPs with 25% release at pH 5...
March 15, 2018: Journal of Microencapsulation
Tanaya Vaidya, Robert M Straubinger, Sihem Ait-Oudhia
PURPOSE: Trastuzumab combined with Doxorubicin (DOX) demonstrates significant clinical activity in human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC). However, emergence of treatment resistance and trastuzumab associated cardiotoxicity remain clinical challenges. In an effort to improve patient outcome, we have developed and evaluated novel tri-functional immunoliposomes (TFIL) that target HER2-receptors on BC cells and CD3-receptors on T-lymphocytes, and deliver DOX...
March 13, 2018: Pharmaceutical Research
George W Pratt, Andy Fan, Bissrat Melakeberhan, Catherine M Klapperich
Proper management of an HIV infection requires that a patient be at least 80-95% adherent to a prescribed drug regimen to avoid poor health outcomes and the development of drug-resistant HIV strains. Clinicians generally monitor adherence habits indirectly through patient self-reporting, pill counting, and electronic drug monitoring. While direct measurement of patient samples like urine for monitoring drug levels is possible, it requires specialized equipment and training that is not readily available in resource-limited settings where the need is greatest...
August 9, 2018: Analytica Chimica Acta
Roland B Walter
There is long-standing interest in drugs targeting the myeloid differentiation antigen CD33 in acute myeloid leukemia (AML). Positive results from randomized trials with the antibody-drug conjugate (ADC) gemtuzumab ozogamicin (GO) validate this approach. Partly stimulated by the success of GO, several CD33-targeted therapeutics are currently in early phase testing. Areas covered: CD33-targeted therapeutics in clinical development include Fc-engineered unconjugated antibodies (BI 836858 [mAb 33.1]), ADCs (SGN-CD33A [vadastuximab talirine], IMGN779), radioimmunoconjugates (225 Ac-lintuzumab), bi- and trispecific antibodies (AMG 330, AMG 673, AMV564, 161533 TriKE fusion protein), and chimeric antigen receptor (CAR)-modified immune effector cells...
March 13, 2018: Expert Opinion on Investigational Drugs
Glenwood D Goss, Everett E Vokes, Michael S Gordon, Leena Gandhi, Kyriakos P Papadopoulos, Drew W Rasco, JuDee S Fischer, Katharine L Chu, William W Ames, Rajendar K Mittapalli, Ho-Jin Lee, Jiewei Zeng, Lisa A Roberts-Rapp, Lise I Loberg, Peter J Ansell, Edward B Reilly, Christopher J Ocampo, Kyle D Holen, Anthony W Tolcher
BACKGROUND: Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific. METHODS: This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III...
March 13, 2018: Cancer
Meghdad Abdollahpour-Alitappeh, Seyed Masoud Hashemi Karouei, Majid Lotfinia, Amir Amanzadeh, Mahdi Habibi-Anbouhi
Rituximab is a chimeric monoclonal antibody directed against B-lymphocyte specific antigen CD20, which is used for the treatment of B-cell malignancies. However, the effectiveness of rituximab is limited partly due to treatment resistance. The aim of this study was to develop rituximab-based antibody drug conjugate (ADC) to enhance rituximab activity. In this study, monomethyl auristatin E (MMAE) was covalently conjugated to dithiothreitol -reduced rituximab via a valine-citrulline peptide linker (rituximab-vcMMAE)...
March 9, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Qun Zhou
BACKGROUND: Glycan-binding proteins are widely distributed in human and play an essential role in biological processes. Their involvements in inflammatory and immune responses make it increasingly likely that the glycan-binding proteins may represent valuable therapeutic targets. OBJECTIVE: The current review aims to provide information on recent advancements in clinical developments of antibodies against glycan-binding proteins as potential targets. RESULTS AND CONCLUSION: There are several therapeutic antibodies being developed targeting glycan-binding proteins, including CD22, CD33, DEC-205, and CD62P, for different diseases...
March 8, 2018: Current Drug Targets
Bo Chen, Diego A Gianolio, James E Stefano, Charlene M Manning, Richard C Gregory, Michelle M Busch, William H Brondyk, Robert J Miller, Pradeep K Dhal
A series of novel multivalent drug linkers (MDLs) containing cytotoxic agents were synthesized and conjugated to antibodies to yield highly potent antibody-drug conjugates (ADCs) with drug/antibody ratios (DARs) higher than those typically reported in the literature (10 vs. ≈4). These MDLs contain two copies of a cytotoxic agent attached to biocompatible scaffolds composed of a branched peptide core and discrete polyethylene glycol (PEG) chains to enhance solubility and decrease aggregation. These drug linkers produced well-defined ADCs, whose DARs could be accurately determined by LC-MS...
March 8, 2018: ChemMedChem
A Choudhry, S M O'Brien
Inotuzumab ozogamicin is an antibody-drug conjugate comprised of a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic agent. Inotuzumab ozogamicin binds to CD22-expressing tumor cells, resulting in apoptotic cell death. Based on the results of the pivotal, phase III INO-VATE trial in acute lymphoblastic leukemia (ALL), approval of inotuzumab ozogamicin was recently granted for the treatment of patients with relapsed or refractory ALL, a group that otherwise has a poor prognosis with standard chemotherapy...
December 2017: Drugs of Today
Khoan Vu, Weiyun Ai
PURPOSE OF REVIEW: Given the rarity of anaplastic large cell lymphoma (ALCL), studies evaluating new therapies have typically grouped ALCL together with other peripheral T cell lymphomas (PTCL). Thus, the treatment paradigm for ALCL largely mirrors that of PTCL in general. In this review, we discuss the current standard of care as well as emerging therapies, including antibody-based drugs, in systemic ALCL as well as primary cutaneous and breast implant-associated ALCL. RECENT FINDINGS: High CD30 expression in ALCL has allowed the use of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, in both systemic and primary cutaneous ALCL...
March 7, 2018: Current Hematologic Malignancy Reports
Xiuhua Kang, Li Zhou, Ya-Mei Jian, Shao-An Lan, Fei Xu
BACKGROUND Human lung cancer is still the leading cause of cancer-related mortality around the world, although a variety of new therapies have been used in the treatment of this disease. Antibody-drug conjugate (ADC) has revolutionized the field of cancer therapy in recent decades. Unlike traditional chemotherapy that damages the healthy cells, ADC first utilizes monoclonal antibodies to bind tumor-specific antigen targets and then deliver a highly potent cytotoxic agent to kill tumor cells. Thus, ADC can benefit cancer patients because this drug has less severe adverse effects...
March 8, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Sandra Jordaan, Olusiji A Akinrinmade, Thomas Nachreiner, Christian Cremer, Krupa Naran, Shivan Chetty, Stefan Barth
Targeted cancer therapy includes, amongst others, antibody-based delivery of toxic payloads to selectively eliminate tumor cells. This payload can be either a synthetic small molecule drug composing an antibody-drug conjugate (ADC) or a cytotoxic protein composing an immunotoxin (IT). Non-human cytotoxic proteins, while potent, have limited clinical efficacy due to their immunogenicity and potential off-target toxicity. Humanization of the cytotoxic payload is essential and requires harnessing of potent apoptosis-inducing human proteins with conditional activity, which rely on targeted delivery to contact their substrate...
March 5, 2018: Biomedicines
Wui K Chong, Virginie Papadopoulou, Paul A Dayton
Microbubble ultrasound contrast agents (UCAs) were recently approved by the Food and Drug administration for non-cardiac imaging. The physical principles of UCAs, methods of administration, dosage, adverse effects, and imaging techniques both current and future are described. UCAs consist of microbubbles in suspension which strongly interact with the ultrasound beam and are readily detectable by ultrasound imaging systems. They are confined to the blood pool when administered intravenously, unlike iodinated and gadolinium contrast agents...
March 5, 2018: Abdominal Radiology
Kiley A Knapp, Eusebio S Pires, Sara J Adair, Arabinda Mandal, Anne M Mills, Walter C Olson, Craig L Slingluff, J Thomas Parsons, Todd W Bauer, Timothy N Bullock, John C Herr
Successful therapeutic options remain elusive for pancreatic cancer. The exquisite sensitivity and specificity of humoral and cellular immunity may provide therapeutic approaches if antigens specific for pancreatic cancer cells can be identified. Here we characterize SAS1B (ovastacin, ASTL , astacin-like), a cancer-oocyte antigen, as an attractive immunotoxin target expressed at the surface of human pancreatic cancer cells, with limited expression among normal tissues. Immunohistochemistry shows that most pancreatic cancers are SAS1Bpos (68%), while normal pancreatic ductal epithelium is SAS1Bneg ...
February 6, 2018: Oncotarget
Sophie Gong, Yuan Li, Wenji Su, Yu Ding, Jiaqi Lu, Kelly Dong, Steve Hood, Wandong Zhang, Georg C Terstappen
Antibody-triggered endocytosis (ATE) is a biological mechanism on which many therapeutic strategies are grounded, such as delivery of antibody-drug conjugates (ADCs). Current methods monitoring ATE include confocal Z-stack analysis, acid wash, antibody quenching, and pH-sensitive dye labeling. However, those generate less quantifiable results with low throughput. Here we report a new method referred to as "paired imaging measurement" to analyze ATE using a quantitative algorithm in conjunction with high-content imaging...
March 1, 2018: SLAS Discovery
Jin-Ju Byeon, Min-Ho Park, Seok-Ho Shin, Byeong Ill Lee, Yuri Park, Jangmi Choi, Nahye Kim, Yeonjae Kang, Young G Shin
A single hybrid affinity-captured-LC-TOF-MS/MS method was developed and applied for the quantification of total antibody, antibody conjugated drug and free payload of antibody drug conjugate (ADC). Adcetris®, one of the valine-citrulline MMAE (vc-MMAE) conjugated ADC, was used as a model ADC compound. A quadratic regression (weighted 1/concentration) was used to fit calibration curves over the concentration range of 30.65-613.00 ng/mL with an equation y=ax2 +bx+c for the acDrug of Adcetris®. The qualification run met the acceptance criteria of ± 25% accuracy and precision values for quality control samples...
March 5, 2018: Biomedical Chromatography: BMC
Eric Sanchez, Edward J Tanenbaum, Saurabh Patil, Mingjie Li, Camilia M Soof, Aleksandra Vidisheva, Gabriel N Waterman, Tara Hekmati, George Tang, Cathy S Wang, Haiming Chen, James Berenson
B-cell maturation antigen (BCMA) is a cell membrane bound tumor necrosis factor receptor family member that is expressed exclusively on late stage normal and malignant B-cells and plasma cells. Addition of two of its ligands, B-cell activating factor and a proliferation inducting ligand, to normal B-cells cause B-cell proliferation and antibody production. Serum BCMA is elevated among patients with multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), and is a prognostic and monitoring tool for these patients...
March 7, 2018: Expert Review of Molecular Diagnostics
Yuan-Chiang Chung, Ching-Ming Chang, Wan-Chen Wei, Ting-Wei Chang, King-Jen Chang, Wei-Ting Chao
Trastuzumab emtansine (T-DM1) is an antibody drug conjugate (ADC) that was recently approved for the treatment of HER-2-positive metastatic breast cancer. The drug sensitivity of ADCs depends mainly on the internalization efficiency of the drug. Caveolin-1 was shown to promote T-DM1 internalization and enhance drug sensitivity. Whether caveolin-1 can be overexpressed to improve T-DM1 efficacy is interesting and has the potential for clinical application. In this study, diabetes drug metformin was investigated in terms of induction of caveolin-1 expression for increased efficacy of subsequent T-DM1 application...
March 2, 2018: Scientific Reports
Anja Mottok, Christian Steidl
Hodgkin lymphoma is considered a prime example of treatment success with cure rates exceeding 80% using modern combined modality therapies. However, especially in adolescents and young adults, treatment-related toxicity and long-term morbidity still represent persistent challenges. Moreover, outcomes in patients with relapsed or refractory disease remain unfavorable in the era of high-dose chemotherapy and stem cell transplantation. Hence, there is a high demand for novel and innovative alternative treatment approaches...
March 2, 2018: Blood
Paul J Bröckelmann, Stephanie Sasse, Andreas Engert
With defined chemo- and radiotherapy and risk-adapted treatment, early-stage classical Hodgkin lymphoma (HL) has become curable in the majority of patients. A major current goal is hence to reduce treatment-related toxicity while maintaining long-term disease control. Patients with early-stage favorable disease, i.e. limited stage without risk factors (RFs), are frequently treated with two cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (2xABVD) followed by 20Gy involved-field or -site radiotherapy (IF/IS-RT)...
March 2, 2018: Blood
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