scholarly journals Novel Antibody Drug Conjugates Targeting Tumor-Associated Receptor Tyrosine Kinase ROR2 by Functional Screening of Fully Human Antibody Libraries Using Transpo-mAb Display on Progenitor B Cells

2018 ◽  
Vol 9 ◽  
Author(s):  
Ina Hellmann ◽  
Lorenz Waldmeier ◽  
Marie-Christine Bannwarth-Escher ◽  
Kseniya Maslova ◽  
Fabian I. Wolter ◽  
...  
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Human Antibody ◽  
Functional Screening ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Libraries ◽  
Antibody Drug

scholarly journals Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

2020 ◽  
Vol 12 ◽  
pp. 175883592092006
Author(s):  
Hang-Ping Yao ◽  
Sreedhar Reddy Suthe ◽  
Xiang-Min Tong ◽  
Ming-Hai Wang
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Targeted Therapeutics ◽  
Antibody Drug Conjugates ◽  
Drug Candidates ◽  
Drug Conjugates ◽  
Ron Receptor ◽  
Antibody Drug

The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

scholarly journals Anti-CD22 and anti-CD79b antibody-drug conjugates preferentially target proliferating B cells

2017 ◽  
Vol 174 (8) ◽  
pp. 628-640 ◽  
Author(s):  
Franklin K Fuh ◽  
Caroline Looney ◽  
Dongwei Li ◽  
Kirsten A Poon ◽  
Randall C Dere ◽  
...  
Keyword(s):  
B Cells ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

scholarly journals Human Antibody Fusion Proteins/Antibody Drug Conjugates in Breast and Ovarian Cancer

2017 ◽  
Vol 44 (5) ◽  
pp. 303-310 ◽  
Author(s):  
Eden R. Padayachee ◽  
Fleury Augustin Nsole Biteghe ◽  
Zaria Malindi ◽  
Dirk Bauerschlag ◽  
Stefan Barth
Keyword(s):  
Ovarian Cancer ◽  
Fusion Proteins ◽  
Human Antibody ◽  
Breast And Ovarian Cancer ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

FcRL5 as a Target of Antibody-Drug Conjugates for the Treatment of Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3836-3836 ◽  
Author(s):  
Andrew G. Polson ◽  
Bing Zheng ◽  
Kristi Elkins ◽  
Jeffery Lau ◽  
Mary Ann T. Go ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cells ◽  
Cell Line ◽  
Research Funding ◽  
Employment Equity ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Equity Ownership ◽  
Antibody Drug

Abstract Abstract 3836 Poster Board III-772 Antibody-drug conjugates (ADCs), potent cytotoxic drugs linked to antibodies via specialized chemical linkers, provide a means to increase the effectiveness of chemotherapy by targeting the drug to neoplastic cells while reducing side effects. Target selection is a key component to the success of an ADC. In addition to expression on the tumor, the target should have limited expression on normal tissues. The most prevalent and best-studied surface antigens on multiple myeloma (MM) cells, CD138, CD38, CD72, and CD56, all have relatively broad expression patterns that may lead to target-dependent toxicities with ADCs. We have previously shown that FcRL5/FcRH5/IRTA2 is expressed only on B-cells and plasma cells. Here we show that FcRL5 is expressed on the surface of MM cells from 85% of patients and thus could be a target for antibody and ADC treatments of MM. As experience in humans with anti-CD20 antibodies suggests that depletion of B-cells does not present a major safety issue, FcRL5 appears to have an excellent expression pattern as an ADC target for MM. Internalization of target antigens is known to increase the efficacy of ADCs and we found that FcRL5 is internalized upon antibody binding, an ideal trait. We made two different ADCs consisting of anti-FcRL5 antibodies 1) conjugated through cysteines to monomethylauristatin E (MMAE) by a maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vcPAB) linker that is designed to be cleaved by cathepsins (Anti-FcRL5-MC-vcPAB-MMAE); and 2) conjugated via lysines to the maytansinoid DM4 through a disulified linker designed to be cleaved by reducing conditions (anti-FcRL5-SPDB-DM4). These ADCs were tested for cell killing in vitro and in xenograft studies using OPM2 cells stably expressing FcRL5. While unconjugated anti-FcRH5 and control ADCs were not effective, anti-FcRL5-MC-vcPAB-MMAE and anti-FcRL5-SPDB-DM4 were effective at killing this MM cell line both in vitro and in vivo. Furthermore, the anti-FcRL5-SPDB-DM4 conjugate was effective in a SCID-rabbit bone model of MM using the LD cell line. These data suggest that FcRL5 ADCs could be an effective treatment for MM. Disclosures: Polson: Genentech, Inc.: Employment, Equity Ownership. Zheng:Genentech, Inc.: Employment, Equity Ownership. Elkins:Genentech, Inc.: Employment, Equity Ownership. Lau:Genentech, Inc.: Employment, Equity Ownership. Go:Genentech, Inc.: Employment, Equity Ownership. Scales:Genentech, Inc.: Employment, Equity Ownership. Yu:Genentech, Inc.: Employment, Equity Ownership. Chesi:Genentech, Inc.: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Bergsagel:Genentech, Inc.: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Ebens:Genentech, Inc.: Employment, Equity Ownership, Patents & Royalties.

scholarly journals Microscale screening of antibody libraries as maytansinoid antibody-drug conjugates

mAbs ◽  
2016 ◽  
Vol 8 (3) ◽  
pp. 513-523 ◽  
Author(s):  
Kalli C. Catcott ◽  
Molly A. McShea ◽  
Carl Uli Bialucha ◽  
Kathy L. Miller ◽  
Stuart W. Hicks ◽  
...  
Keyword(s):  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Libraries ◽  
Antibody Drug

Fcμ-Receptor (FcμR; TOSO/FAIM3) Mediated Internalization of Antibody-Drug Conjugates: A Novel Approach to Selectively Target Chronic Lymphocytic Leukemia Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 734-734
Author(s):  
Berengere Vire ◽  
Alexandre David ◽  
Joshua D Thomas ◽  
Terrence R Burke ◽  
Christoph Rader ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Cell Killing ◽  
Lymphocytic Leukemia ◽  
Endocytic Pathway ◽  
Protein Scaffold ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Abstract Abstract 734 The therapeutic principle of antibody-drug conjugates (ADCs) in cancer relies on an antibody to deliver a cytotoxic agent into malignant cells that express a tumor-associated antigen. Recent progress in the field has shown that the use of such conjugates can increase drug activity and reduce cytotoxicity through selective targeting. Recently, TOSO/FAIM3 was identified as the long sought FcR for IgM (FcμR). FcμR is a transmembrane protein expressed on CD19+ B cells, on some CD4+/CD8+ T cells, and weakly on CD56+/CD3− NK cells. We and others have shown that FcμR is consistently overexpressed on chronic lymphocytic leukemia (CLL) cells compared to normal B-cells. In addition, we detected FcμR expression in the mantle cell lymphoma cell line Mino. Using immunofluorescence staining, we found that FcμR can rapidly internalize IgM and transport it through the endocytic pathway to the lysosome. Interestingly, aggregation of FcμR with IgM lead to rapid internalization (>80% internalized within 5 minutes, n=5) whereas mAb bound FcμR was not internalized (n=3). Because of its restricted expression on CLL cells, its cell surface localization and its rapid internalization, FcμR represents an excellent target to deliver a cytotoxic drug into CLL cells using an ADC. To make use of the rapid internalization of FcμR when bound by the Fc-portion of IgM, we engineered a protein scaffold derived from the CH3-CH4 IgM constant region, and inserted a C-terminal selenocysteine, that allows site specific and covalent conjugation of drugs to the protein scaffold. Using gel filtration, we found that purified CH3-CH4 exists mostly as a multimer including pentameric and hexameric forms, similar to native IgM. First, we verified that the CH3-CH4 protein scaffold also binds FcμR, is internalized and addressed to the lysosomes. Next, we conjugated the CH3-CH4 protein scaffold to cemadotin, a synthetic anti-mitotic agent that inhibits tubulin polymerization. This CH3-CH4-cemadotin conjugate was designed to specifically release the drug inside the cell by inserting a peptide linker that can by cleaved by cathepsin B in the lysosomal compartment. In vitro cell killing showed that this CH3-CH4-cemadotin conjugate potently and selectively killed FcμR expressing cells (IC(50) <0.16 μM) while it was about 200-fold less efficient for cells with undetectable FcμR (IC(50) >31 μM). Control experiments showed equal, i.e. non-selective cytotoxicity of free cemadotin against FcμR expressing and non-expressing cells and absence of cell killing with the unconjugated CH3-CH4 protein scaffold. Taken together, these data identify FcμR as a promising therapeutic target in CLL and possibly select other malignanices. IgM-derived scaffolds constitute ideal carriers for drugs or toxins as they are rapidly internalized. In addition, trafficking of IgM scaffolds to the lysosome provides an additional layer of selectivity as a precursor inactive drug can be activated through lysosomal peptidases. Ongoing efforts aim to test modifications of the scaffold and evaluate additional cytotoxic drugs. Furthermore, we are scaling up production of the lead scaffold drug conjugate in order to test its efficacy in xenograft mouse models. This work was supported by the Intramural Research Program of the National, Heart, Lung and Blood Institute. Disclosures: No relevant conflicts of interest to declare.

ASCO-GU 2019: Metastasierte Urothelkarzinome

2019 ◽  
Vol 10 (03) ◽  
pp. 140-141
Author(s):  
Alexander Kretzschmar
Keyword(s):  
San Francisco ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Chapel Hill ◽  
Antibody Drug

Die Therapielandschaft des metastasierten Urothelkarzinoms hat sich seit der Zulassung der ersten Immun-Checkpoint-Inhibitoren verändert. Die neuen Therapien sind deutlich effektiver, allerdings erreichen die Responseraten der neuen Therapien nur bis zu etwa 30 %, beklagte Prof. Matthew Milowsky, Chapel Hill/USA, auf einer Oral Abstract Session auf dem ASCO-GU. In San Francisco gaben erste Vorträge und Poster bereits einen Einblick, wovon diejenigen Patienten profitieren könnten, die auf die etablierten Chemotherapien und die neuen Immuntherapien nicht ansprechen. Manche Onkologen sprechen bereits von der „Post-Checkpoint-Ära”. Als Kandidaten werden vor allem Antikörper-Wirkstoff-Konjugate (antibody-drug conjugates; ADC) gehandelt – und zwar nicht nur zur Therapie des metastasierten Blasenkarzinoms.

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