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Antibody drug conjugation

George B McDonald, James W Freston, James L Boyer, Laurie D DeLeve
BACKGROUND AND RATIONALE: Treatment of hematologic malignancy with antibody-drug conjugates (ADC) may cause liver injury. ADCs deliver a toxic moiety into antigen-expressing tumor cells but may also injure hepatic sinusoids (Sinusoidal Obstruction Syndrome, SOS). We studied patients who received an anti-CD22-calicheamicin conjugate (inotuzumab ozogamicin) to gain insight into mechanisms of sinusoidal injury, as there are no CD22+ cells in the normal liver but non-specific uptake of ADCs by liver sinusoidal endothelial cells...
August 18, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Michael C Comiskey, Matthew C Dallos, Charles G Drake
Immunotherapy is rapidly transforming cancer care across a range of tumor types. Although Sipuleucel-T represented the first successful vaccine for the treatment of established cancer, other immunotherapeutic approaches for prostate cancer such as checkpoint inhibitors have been relatively disappointing to date. However, significant promise is on the horizon as there is a wide array trials evaluating immunotherapy in prostate cancer patients. These include both immune checkpoint inhibitors and antigen-specific approaches including vaccines, antibody-drug conjugates, and antitumor antibodies...
August 18, 2018: Current Oncology Reports
Panagiotis J Vlachostergios, Christopher D Jakubowski, Muhammad J Niaz, Aileen Lee, Charlene Thomas, Amy L Hackett, Priyanka Patel, Naureen Rashid, Scott T Tagawa
Urothelial carcinoma (UC) is characterized by expression of a plethora of cell surface antigens, thus offering opportunities for specific therapeutic targeting with use of antibody-drug conjugates (ADCs). ADCs are structured from two major constituents, a monoclonal antibody (mAb) against a specific target and a cytotoxic drug connected via a linker molecule. Several ADCs are developed against different UC surface markers, but the ones at most advanced stages of development include sacituzumab govitecan (IMMU-132), enfortumab vedotin (ASG-22CE/ASG-22ME), ASG-15ME for advanced UC, and oportuzumab monatox (VB4-845) for early UC...
July 30, 2018: Bladder Cancer
Oleksandr Koniev, Igor Dovgan, Brigitte Renoux, Anthony Ehkirch, Jitka Eberova, Sarah Cianférani, Sergii Kolodych, Sébastien Papot, Alain Wagner
The reduction-rebridging strategy is a powerful method for the preparation of stable and homogeneous antibody-drug conjugates (ADCs). In this communication, we describe the development of the arylene-dipropiolonitrile (ADPN) functional group for the rebridging of reduced disulphide bonds and its application in the preparation of potent and selective ADCs.
May 1, 2018: MedChemComm
Yun Hu, Zongmin Zhao, Theresa Harmon, Paul R Pentel, Marion Ehrich, Chenming Zhang
Polyethylene glycol (PEG) has long been used in nanoparticle-based drug or vaccine delivery platforms. In this study, nano-nicotine vaccines (NanoNicVac) were PEGylated to different degrees to investigate the impact of PEG on the immunological efficacy of the vaccine. Hybrid nanoparticles with various degrees of PEGylation (2.5%-30%) were assembled. It was found that 30% PEGylation resulted in a hybrid nanoparticle of a compromised core-shell structure. A higher concentration of PEG also led to a slower cellular uptake of hybrid nanoparticles by dendritic cells...
August 7, 2018: Biomaterials
Asen Bagashev, Elena Sotillo, Chih-Hang Anthony Tang, Kathryn L Black, Jessica Perazzelli, Steven H Seeholzer, Yair Argon, David M Barrett, Stephan A Grupp, Chih-Chi Andrew Hu, Andrei Thomas-Tikhonenko
We have previously described a mechanism of acquired resistance of B-cell acute lymphoblastic leukemia to CD19-directed chimeric antigen receptor T-cell (CART) immunotherapy. It was based on in-frame insertions in or skipping of CD19 exon 2. To distinguish between epitope loss and defects in surface localization, we used retroviral transduction and genome editing to generate cell lines expressing CD19 exon 2 variants (CD19ex2vs) bearing VSV-G tags. These lines were negative by live-cell flow cytometry with an anti-VSV-G antibody and resistant to killing by VSV-G directed antibody-drug conjugates (ADC), suggestive of a defect in surface localization...
August 13, 2018: Molecular and Cellular Biology
(no author information available yet)
No abstract text is available yet for this article.
August 10, 2018: Cornea
Timothy Robson, Deepan S H Shah, Alexandra S Solovyova, Jeremy H Lakey
Functional protein-gold nanoparticle (AuNP) conjugates have a wide variety of applications including biosensing and drug delivery. Correct protein orientation, which is important to maintain functionality on the nanoparticle surface, can be difficult to achieve in practice, and dedicated protein scaffolds have been used on planar gold surfaces to drive the self-assembly of oriented protein arrays. Here we use the transmembrane domain of Escherichia coli outer membrane protein A (OmpATM ) to create protein-AuNP conjugates...
July 27, 2018: ACS applied nano materials
Channay Naidoo, Cherie Ann Kruger, Heidi Abrahamse
This review article is based on specifically targeted nanoparticles that have been used in the treatment of melanoma. According to the Skin Cancer Foundation, within 2017 an estimated 9730 people will die due to invasive melanoma. Conventional treatments for nonmalignant melanoma include surgery, chemotherapy, and radiation. For the treatment of metastatic melanoma, 3 therapeutic agents have been approved by the Food and Drug Administration: dacarbazine, recombinant interferon α-2b, and high-dose interleukin 2...
January 1, 2018: Technology in Cancer Research & Treatment
Ruud Ubink, Eef Hc Dirksen, Myrthe Rouwette, Ebo Sijbren Bos, Ingrid Janssen, David F Egging, Eline M Loosveld, Tanja A van Achterberg, Kim Berentsen, Miranda M C van der Lee, Francis Bichat, Olivier Raguin, Monique A J van der Vleuten, Patrick G Groothuis, Wim H A Dokter
Carboxylesterase 1c (CES1c) is responsible for linker-drug instability and poor pharmacokinetics (PK) of several antibody-drug conjugates (ADCs) in mouse, but not in monkey or human. Preclinical development of these ADCs could be improved if the PK in mice would more closely resemble that of human and is not affected by an enzyme that is irrelevant for humans. SYD985, a HER2-targeting ADC based on trastuzumab and linker-drug vc-seco-DUBA is also sensitive to CES1c. In the present studies, we first focused on the interaction between CES1c and SYD985 by size- exclusion chromatography, Western blotting and LC-MS/MS analysis, using recombinant CES1c and plasma samples...
August 9, 2018: Molecular Cancer Therapeutics
Kathleen N Moore, David M O'Malley, Ignace Vergote, Lainie P Martin, Antonio Gonzalez-Martin, Karim Malek, Michael J Birrer
PURPOSE: To evaluate the safety profile and preliminary antitumor activity of mirvetuximab soravtansine when administered in combination with carboplatin to relapsed ovarian cancer patients. METHODS: Patients with recurrent, platinum-sensitive epithelial ovarian or fallopian tube cancer were enrolled. Eligibility included a minimum requirement of tumor FRα positivity (≥25% of cells with ≥2+ staining intensity). Patients received escalating doses of mirvetuximab soravtansine and carboplatin on day 1 of a 21-day cycle (once every 3 weeks)...
August 6, 2018: Gynecologic Oncology
Zaina T Al-Salama
The intravenous CD22-directed antibody drug conjugate inotuzumab ozogamicin (Besponsa® ) is approved in several countries including in the USA, EU and Japan, as monotherapy for the treatment of adults with relapsed/refractory B-cell acute lymphoblastic leukaemia (ALL). In adults with relapsed/refractory B-cell ALL who had received one or two prior treatment regimens, inotuzumab ozogamicin was associated with significantly higher rates of complete remission (including complete remission with incomplete haematological recovery) [CR/CRi] than standard therapy in the pivotal INO-VATE ALL trial...
August 9, 2018: Targeted Oncology
Ilana R Yurkiewicz, Lori Muffly, Michaela Liedtke
Despite improved rates of remission and cure in newly diagnosed adult acute lymphoblastic leukemia (ALL), the prognosis for patients with relapsed or refractory disease remains poor and the 5-year overall survival rate after relapse is under 10%. A recent paradigm shift has focused on the promise of targeted immunotherapy rather than standard chemotherapy, as ALL blast cells express a variety of antigens, and monoclonal antibodies may be developed to identify and destroy the leukemic cells. Inotuzumab ozogamicin is a CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin...
2018: Drug Design, Development and Therapy
Shun Xin Wang-Lin, Chenguang Zhou, Amrita V Kamath, Kyu Hong, Neelima Koppada, Ola M Saad, Montserrat Carrasco-Triguero, Cyrus Khojasteh, Rong Deng
DSTA4637A, a THIOMAB™ antibody-antibiotic conjugate targeting Staphylococcus aureus, has shown promising bactericidal activity in a mouse model. DSTA4637A consists of a monoclonal anti-S. aureus antibody with an average of two rifalogue antibiotic molecules, dmDNA31, linked to its light chains. The goal of this study was to develop a minimal physiologically-based pharmacokinetic (mPBPK) model to characterize the pharmacokinetic (PK) properties of three analytes of DSTA4637A (i.e., total antibody, antibody-conjugated dmDNA31, and unconjugated dmDNA31) in mice, and to predict pharmacokinetics of DSTA4637A analytes in humans, as well as to provide an initial assessment for potential PK drug-drug interactions (DDI) in clinical trials via cross-species scaling of the mPBPK model...
August 6, 2018: MAbs
Chengqiong Mao, Yan Zhao, Fang Li, Zibo Li, Shaomin Tian, Waldemar Debinski, Xin Ming
Drug resistance remains a formidable challenge to cancer therapy. P-glycoprotein (Pgp) contributes to multidrug resistance in numerous cancers by preventing accumulation of anticancer drugs in cancer cells. Strategies to overcome this resistance have been vigorously sought for over 3 decades, yet clinical solutions do not exist. The main reason for the failure is lack of cancer specificity of small-molecule Pgp inhibitors, thus causing severe toxicity in normal tissues. In this study, Pgp-targeted photodynamic therapy (PDT) was developed to achieve superior cancer specificity through antibody targeting plus locoregional light activation...
August 3, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Kathleen W Phelan, Anjali S Advani
PURPOSE OF REVIEW: Treatment options for patients with acute lymphoblastic leukemia (ALL) beyond standard chemotherapy have grown significantly in recent years. In this review, we highlight new targeted therapies in ALL, with an emphasis on immunotherapy. RECENT FINDINGS: Major advances include antibody-based therapies, such as naked monoclonal antibodies, antibody-drug conjugates and bispecific T cell engaging (BiTE) antibodies, as well as adoptive cellular therapies such as chimeric antigen receptor (CAR) T cells...
August 2018: Current Hematologic Malignancy Reports
Lei Wang, Quanren Wang, Mingzhao Gao, Li Fu, Yun Li, Haitian Quan, Liguang Lou
Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that has been approved for the treatment of HER2-positive metastatic breast cancer. Despite the remarkable efficacy of T-DM1 in many patients, resistance to this therapeutic has emerged as a significant clinical problem. In the current study, we used BT-474/KR cells, a T-DM1-resistant cell line established from HER2-positive BT-474 breast cancer cells, as a model to investigate mechanisms of T-DM1 resistance and explore effective therapeutic regimens...
August 4, 2018: Cancer Science
Mahmudul Hasan, Safaet Alam, Saikat Kumar Poddar
Cancer is one of the deadly diseases which is characterized by unchecked cell division or abnormal cell growth due to the incapability of cell cycle arrest. As the treatment for this is to kill the cancerous cells the main challenge for scientists is to direct the cell killing to cancerous cells while leaving the normal cells unharmed. Antibody-drug conjugates (ADC) are one such targeted anti-cancer therapy. It is an effective drug delivery system that utilizes the targeting action of antibody along with cell death by potent cytotoxic agent, linked up with one another by a linker molecule and thus helps to reduce toxicity to non-target cells, ensure broad therapeutic window and overcome multi-drug resistance...
August 1, 2018: Current Clinical Pharmacology
Chen Wang, Pan Xu, Luyu Zhang, Jing Huang, Kongkai Zhu, Cheng Luo
Since Human Genome Project (HGP) revealed the heterogeneity of individuals, precision medicine that proposes the customized healthcare has become an intractable and hot research. Meanwhile, as the Precision Medicine Initiative launched, precision drug design which aims at maximizing therapeutic effects while minimizing undesired side effects for an individual patient has entered a new stage. One of the key strategies of precision drug design is target based drug design. Once a key pathogenic target is identified, rational drug design which constitutes the major part of precision drug design can be performed...
2018: Frontiers in Pharmacology
Heng Liang Tan, Charlene Yong, Bao Zhu Tan, Wey Jia Fong, Jayanthi Padmanabhan, Angela Chin, Vanessa Ding, Ally Lau, Lu Zheng, Xuezhi Bi, Yuansheng Yang, Andre Choo
Monoclonal antibodies (mAbs) are used as targeted therapies against cancers. These mAbs kill cancer cells via various mechanisms of actions. In this study, human embryonic stem cells (hESCs) was used as the immunogen to generate a panel of antibodies. From this panel of mAbs, A19 was found to bind both hESC and various cancer cell lines. The antigen target of A19 was identified as Erbb-2 and glycan analysis showed that A19 binds to a N-glycan epitope on the antigen. A19 was elucidated to internalize into cancer cells following binding to Erbb-2 and hence developed as an antibody-drug conjugate (ADC)...
August 2, 2018: Scientific Reports
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