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Kin Man Au, Ashutosh Tripathy, Carolina Pe-I Lin, Kyle Wagner, Seungpyo Hong, Andrew Z Wang, Steven I Park
Non-Hodgkin lymphoma (NHL) is one of the most common types of hematologic malignancies. Pretargeted radioimmunotherapy (PRIT), the sequential administration of a bispecific antibody-based primary tumor-targeting component followed by a radionucleotide-labeled treatment effector, has been developed to improve the treatment efficacy and to reduce the side effects of conventional RIT. Despite the preclinical success of PRIT, clinical trials revealed that the immunogenicity of the bispecific antibody as well as the presence of competing endogenous effector molecules often compromised the treatment...
February 27, 2018: ACS Nano
Juan Ma, Jing Ge, Xin Xue, Weigang Xiu, Pan Ma, Ximing Sun, Man Zhang
In the present study, we aimed to investigate whether EGFR or HER2 may serve as a target for T cell-mediated immunotherapy against human bladder cancer. Expression of EGFR and HER2 was detected on the surface of bladder cancer cells, including Pumc-91 and T24 cells, and their chemotherapeutic drug-resistant counterparts. Activated T cells (ATCs) were generated from healthy PBMCs that were stimulated by the combination of anti-CD3 monoclonal antibody and anti‑CD28 monoclonal antibody in the presence of interleukin-2 for 14 days...
March 2018: Oncology Reports
Kevin Bielamowicz, Kristen Fousek, Tiara T Byrd, Hebatalla Samaha, Malini Mukherjee, Nikita Aware, Meng-Fen Wu, Jordan S Orange, Pavel Sumazin, Tsz-Kwong Man, Sujith K Joseph, Meenakshi Hegde, Nabil Ahmed
Background: Glioblastoma (GBM) is the most common primary malignant brain cancer, and is currently incurable. Chimeric antigen receptor (CAR) T cells have shown promise in GBM treatment. While we have shown that combinatorial targeting of 2 glioma antigens offsets antigen escape and enhances T-cell effector functions, the interpatient variability in surface antigen expression between patients hinders the clinical impact of targeting 2 antigen pairs. This study addresses targeting 3 antigens using a single CAR T-cell product for broader application...
March 27, 2018: Neuro-oncology
Sarah M Cheal, Edward K Fung, Mitesh Patel, Hong Xu, Hong-Fen Guo, Pat B Zanzonico, Sebastien Monette, K Dane Wittrup, Nai-Kong V Cheung, Steven M Larson
Radioimmunotherapy of solid tumors using antibody-targeted radionuclides has been limited by low therapeutic indices (TIs). We recently reported a novel 3-step pretargeted radioimmunotherapy (PRIT) strategy based on a glycoprotein A33 (GPA33)-targeting bispecific antibody and a small-molecule radioactive hapten, a complex of177 Lu and S -2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (177 Lu-DOTA-Bn), that leads to high TIs for radiosensitive tissues such as blood (TI = 73) and kidney (TI = 12)...
November 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Haleh Saber, Ramadevi Gudi, Michael Manning, Emily Wearne, John K Leighton
As sub-therapeutic doses are not medically justifiable in patients with cancer, we retrospectively analyzed data on immune activating products, to assess approaches used in first-in-human (FIH) dose selection, the utility of animal toxicology studies in dose selection, and the length of time to complete FIH trials. The information collected included pharmacology and toxicology data, FIH dose and rationale, and dose-finding trial design. We used the principles of the Hill equation to estimate the FIH doses for antibodies and compared them to the doses administered to patients with acceptable toxicities...
November 2016: Regulatory Toxicology and Pharmacology: RTP
Florence T H Wu, Shan Man, Ping Xu, Annabelle Chow, Marta Paez-Ribes, Christina R Lee, Steven R Pirie-Shepherd, Urban Emmenegger, Robert S Kerbel
Antiangiogenic tyrosine kinase inhibitors (TKI) that target VEGF receptor-2 (VEGFR2) have not been effective as adjuvant treatments for micrometastatic disease in phase III clinical trials. Angiopoietin-2 (Ang2) is a proangiogenic and proinflammatory vascular destabilizer that cooperates with VEGF. The purpose of this study was to test whether CVX-060 (an Ang2-specific CovX-body) can be combined with VEGFR2-targeting TKIs (sunitinib or regorafenib) to successfully treat postsurgical metastatic disease in multiple orthotopically implanted human tumor xenograft and syngeneic murine tumor models...
December 1, 2016: Cancer Research
Juan Ma, Pan Ma, Chenghai Zhao, Xin Xue, Huamin Han, Changzhen Liu, Hua Tao, Weigang Xiu, Jia Cai, Man Zhang
Targeting B7-H3 over-expressed tumor cells with anti-B7-H3 monoclonal antibodies inhibits tumor growth. Here we demonstrated the expression of B7 family homologue 3 (B7-H3) in a wide range of human tumor cells and further investigated whether B7-H3 could be served as a target for T-cell mediated immunotherapy against human cancers. The specific cytotoxic activity of activated T cell (ATC) armed with a novel anti-CD3 x anti-B7-H3 bispecific antibody (B7-H3Bi-Ab) against tumor cell was evaluated in vitro and in vivo...
May 17, 2016: Oncotarget
Yan Zhou, Lan-Tu Gou, Zhi-Hui Guo, Hai-Rong Liu, Jiang-Man Wang, Shu-Xian Zhou, Jin-Liang Yang, Xiao-An Li
The use of a bispecific antibody (BsAb) is a promising and highly specific approach to cancer therapy. In the present study, a fully human recombinant single chain variable fragment BsAb against human epidermal growth factor receptor (HER)2 and cluster of differentiation (CD)3 was constructed with the aim of developing an effective treatment for breast cancer. HER2/CD3 BsAb was expressed in Chinese hamster ovary cells and purified via nickel column chromatography. Flow cytometry revealed that the HER2/CD3 BsAb was able to specifically bind to HER2 and CD3‑positive cells...
July 2015: Molecular Medicine Reports
Ryan Wong, Chris Pepper, Paul Brennan, Dirk Nagorsen, Stephen Man, Chris Fegan
Chronic lymphocytic leukemia is an incurable B-cell malignancy that is associated with tumor cell-mediated T-cell dysfunction. It therefore represents a challenging disease for T-cell immunotherapeutics. The CD19/CD3 bi-specific antibody construct blinatumomab (AMG103 or MT103) has been tested clinically in non-Hodgkin's lymphoma and acute lymphoblastic leukemia but has not been assessed in chronic lymphocytic leukemia. We investigated whether blinatumomab could overcome T-cell dysfunction in chronic lymphocytic leukemia in vitro...
December 2013: Haematologica
Lawrence G Lum, Archana Thakur
Bispecific antibodies (BiAbs) offer a unique opportunity to redirect immune effector cells to kill cancer cells. BiAbs combine the benefits of different binding specificities of two monoclonal antibodies (mAbs) into a single construct. This unique feature of BiAbs enables approaches that are not possible with single mAbs. Advances in antibody engineering and antigen profiling of malignant cells have led to the development of a number of BiAb formats and their combinations for redirecting effector cells to tumor targets...
December 1, 2011: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
P D Griffiths
No abstract text is available yet for this article.
July 2009: Reviews in Medical Virology
Jenny Bostrom, Shang-Fan Yu, David Kan, Brent A Appleton, Chingwei V Lee, Karen Billeci, Wenyan Man, Franklin Peale, Sarajane Ross, Christian Wiesmann, Germaine Fuh
The interface between antibody and antigen is often depicted as a lock and key, suggesting that an antibody surface can accommodate only one antigen. Here, we describe an antibody with an antigen binding site that binds two distinct proteins with high affinity. We isolated a variant of Herceptin, a therapeutic monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2), on the basis of its ability to simultaneously interact with vascular endothelial growth factor (VEGF). Crystallographic and mutagenesis studies revealed that distinct amino acids of this antibody, called bH1, engage HER2 and VEGF energetically, but there is extensive overlap between the antibody surface areas contacting the two antigens...
March 20, 2009: Science
Maria Amann, Klaus Brischwein, Petra Lutterbuese, Larissa Parr, Laetitia Petersen, Grit Lorenczewski, Eva Krinner, Sandra Bruckmeier, Sandra Lippold, Roman Kischel, Ralf Lutterbuese, Peter Kufer, Patrick A Baeuerle, Bernd Schlereth
EpCAM (CD326) is one of the most frequently and highly expressed tumor-associated antigens known and recently has also been found on cancer stem cells derived from human breast, colon, prostate, and pancreas tumors. However, like many other tumor-associated antigens used for antibody-based immunotherapeutic approaches, EpCAM is expressed on normal tissues including epithelia of pancreas, colon, lung, bile ducts, and breast. To assess the therapeutic window of an EpCAM/CD3-bispecific single-chain antibody construct of the bispecific T-cell engager (BiTE) class, we constructed murine surrogate of MT110 (muS110) from single-chain antibodies specific for murine EpCAM and CD3 antigens...
January 1, 2008: Cancer Research
Suet Yi Leung, Siu Tsan Yuen, Kent-Man Chu, Jonathan A Mathy, Rui Li, Annie S Y Chan, Simon Law, John Wong, Xin Chen, Samuel So
BACKGROUND & AIMS: Gastric cancer is one of the major cancers worldwide. Expression profiling has proven useful in delineating novel prognostic markers in various cancer types. We previously analyzed gene-expression patterns in 90 gastric adenocarcinomas by using complementary DNA microarrays and prioritized a list of genes whose expression levels predict patient outcome. METHODS: We identified a specific gene of interest, chemokine (C-C motif) ligand 18 (CCL18), on the basis of a high absolute standardized log Cox hazard ratio, a high variance in expression among all tumor samples, and putative biologic function...
August 2004: Gastroenterology
de Leij L, Molema, Helfrich, Kroesen
Immunotherapy is a powerful anti-cancer treatment modality. However, despite numerous encouraging results obtained in pre-clinical studies, a definite breakthrough towards an established clinical treatment modality has as yet not occurred. Antibodies against tumor antigens have been shown to localise at the site of the tumor, but inadequate triggering of immune effector mechanisms have thwarted clinical efficacy thus far. Cellular immunotherapy has been hampered by limitations such as lack of specificity, down-regulation of major histocompatibility complex (MHC)-expression or Fas ligand up-regulation on tumor cells...
April 6, 1998: Advanced Drug Delivery Reviews
L A Rund, B K Cho, T C Manning, P D Holler, E J Roy, D M Kranz
A variety of immunological approaches to cancer treatment are currently being explored. These include strategies designed to enhance or redirect the activity of T cells against tumors. Bispecific antibodies comprise a class of agents capable of redirecting T cells by binding to a tumor antigen and the T-cell receptor (TCR). In vivo pre-clinical testing of bispecific antibodies against human tumors has to date been limited to the use of immunodeficient mice that receive the bispecific agent, activated human effector T cells, and human tumor cells...
September 24, 1999: International Journal of Cancer. Journal International du Cancer
D M Kranz, T C Manning, L A Rund, B K Cho, M M Gruber, E J Roy
It has been known for some time that mammalian immune systems are capable of eliminating large tumor burdens. Redirecting the immune response of a patient to an established tumor has now become the focus of various therapeutic strategies. In this report, two projects toward this goal are described. The first project involves the development of a transgenic mouse model for T cell directed therapeutics. These mice express specific T cell receptor alpha and beta transgenes on a background in which the recombinational-activating-gene-1 (RAG) has been knocked out...
April 30, 1998: Journal of Controlled Release: Official Journal of the Controlled Release Society
H Zhu, R K Jain, L T Baxter
UNLABELLED: The limited success of the sole use of monoclonal antibodies for cancer detection and treatment has led to the development of multistep methods using antibodies in conjunction with low molecular weight agents. For tumor pretargeting, it is important to optimize dose and schedule of relevant agents and to understand barriers to targeted delivery. Here, we address these issues for the anti-carcinoembryonic antigen bifunctional antibody-hapten and the streptavidinylated antibody-biotin systems using a recently developed physiologically based pharmacokinetic model...
January 1998: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
I A Haagen, A J Geerars, M R Clark, J G van de Winkel
Rat mAbs receive considerable interest for immunologic intervention in man. The rat IgG2b isotype has previously been found to be optimally active both in vivo and in vitro. We found that both a rat IgG2b CD3 mAb and a monovalent hybrid rat IgG2b-mouse IgG1 bispecific Ab triggered T cell activation in PBMC. Inhibition analyses with mAb blocking different human IgG Fc receptors (Fc gamma R) showed a dimorphic pattern. In donors expressing an Fc gamma RIIa-R/R131 allotype (previously defined on the basis of interaction with mouse (m) IgG1 as "high responder") anti-Fc gamma RI mAb 197 inhibited rat IgG2b induced T cell mitogenesis almost completely...
February 15, 1995: Journal of Immunology: Official Journal of the American Association of Immunologists
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