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Identification and therapeutic targeting of GPR20, selectively expressed in gastrointestinal stromal tumorswith DS-6157a, a first-in-class antibody-drug conjugate
Iida K, Abdelhamid Ahmed AH, Nagatsuma AK, Shibutani T, Yasuda S, Kitamura M, Hattori C, Abe M, Hasegawa J, Iguchi T, Karibe T, Nakada T, Inaki K, Kamei R, Abe Y, Nomura T, Andersen JL, Santagata S, Hemming ML, George S, Doi T, Ochiai A, Demetri GD, Agatsuma T (2021) Identification and therapeutic targeting of GPR20, selectively expressed in gastrointestinal stromal tumorswith DS-6157a, a first-in-class antibody-drug conjugate. Cancer Discov 11(6):1508-1523. doi: 10.1158/2159-8290.Cd-20-1434
Objective: Introduce DS-6157a, an anti-GPR20 antibody-drug therapeutic for gastrointestinal stromal tumors (GIST).
Summary: The only approved treatments for GIST are currently tyrosine kinase inhibitors (TKI) which can be problematic. They lead to secondary resistance mutations in KIT or PDGFRA and disease progression. The authors identified G protein-coupled receptor 20 (GPR20) as a non-tyrosine kinase target and assessed its expression in cell lines, xenografts, and clinical samples. Preclinical pharmacokinetics and safety profile support its development as a novel GIST therapy.
Usage: Internalization activity of anti-GPR20 mAbs were evaluated by using Rat-ZAP. GPR20-expressing 293T cells were plated at 2500 cells/well in 96-well plates. Cells were treated with dilutions of various anti-GPR20 and 500 ng/ml of Rat-ZAP for 3 days. The percentage of living cells were measured using a CellTiter-Glo Luminescent Cell Viability Assay.
Related Products: Rat-ZAP (Cat. #IT-26)
Autosomal recessive osteopetrosis: mechanisms and treatments
Penna S, Villa A, Capo V (2021) Autosomal recessive osteopetrosis: mechanisms and treatments. Dis Model Mech 14(5):dmm048940. doi: 10.1242/dmm.048940
Summary: Autosomal recessive osteopetrosis (ARO) is a severe inherited bone disease characterized by defective osteoclast resorption or differentiation. Novel therapeutic approaches are needed for ARO patients. The authors review preclinical and proof-of-concept studies, such as gene therapy, systematic administration of deficient protein, in utero Hematopoietic stem cell transplantation (HSCT) and gene editing.
Usage: Efficacy in HSCT conditioning was demonstrated with CD45.2-SAP (biotinylated Anti-CD45 mixed with Streptavidin-ZAP). In mice, CD45.2–SAP preserved normal bone marrow architecture compared to total body irradiation, which instead reduced vascular integrity and bone marrow cellularity. Mice conditioned with CD45.2–SAP rapidly recovered their peripheral myeloid cells and had a survival advantage when exposed to infections (3 mg/kg iv; Palchaudhuri et al.). Additionally, conditioning with CD45.2–SAP resulted in significant chimerism after transplantation, even in a pathological mouse model (3 mg/kg iv; Castiello et al.).
Related Products: Streptavidin-ZAP (Cat. #IT-27)
See Also:
- Palchaudhuri R et al. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat Biotechnol 34:738-745, 2016.
- Castiello MC et al. Efficacy and safety of anti-CD45-saporin as conditioning agent for RAG deficiency. J Allergy Clin Immunol 147(1):309-320.e6, 2021.
Activated factor X targeted stored in platelets as an effective gene therapy strategy for both hemophilia A and B
Wang D, Shao X, Wang Q, Pan X, Dai Y, Yao S, Yin T, Wang Z, Zhu J, Xi X, Chen Z, Chen S, Zhang G (2021) Activated factor X targeted stored in platelets as an effective gene therapy strategy for both hemophilia A and B. Clin Transl Med 11(3):e375. doi: 10.1002/ctm2.375
Summary: Treatment of hemophiliacs with inhibitors remains challenging, and new treatments are in urgent need. Coagulation factor X plays a critical role in downstream blood coagulation cascade, which could serve as a bypassing agent for hemophilia therapy. Target expression of the FXa precursor to platelets can generate a storage pool of FXa in platelet α-granules, the platelet-stored FXa is effective in treating HA and HB with inhibitors, suggesting that this could be a novel choice for hemophilia patients with inhibitors.
Usage: A single dose of CD45.2-SAP (biotinylated Anti-CD45 mixed with Streptavidin-ZAP) enabled efficient engraftment of donor cells (> 90%) and full correction of sickle-cell anemia. (3 mg/kg iv; Palchaudhuri et al.).
Related Products: Streptavidin-ZAP (Cat. #IT-27)
Bone marrow-derived myeloid progenitors in the leptomeninges of adult mice
Koeniger T, Bell L, Mifka A, Enders M, Hautmann V, Mekala SR, Kirchner P, Ekici AB, Schulz C, Wörsdörfer P, Mencl S, Kleinschnitz C, Ergün S, Kuerten S (2021) Bone marrow-derived myeloid progenitors in the leptomeninges of adult mice. Stem Cells 39(2):227-239. doi: 10.1002/stem.3311
Summary: This report confirms the presence of myeloid progenitors at the meningeal border of the brain and lays the foundation to unravel their possible functions in CNS surveillance and local immune cell production. Compared to bone marrow transfer after whole-body irradiation, chimerism developed more slowly in the CD45-SAP (biotinylated anti-CD45 mixed with Streptavidin-ZAP) model and only reached around 50% in the blood myeloid compartment 15 weeks after transplantation.
Related Products: Streptavidin-ZAP (Cat. #IT-27)
Identification of prostaglandin F2 receptor negative regulator (PTGFRN) as an internalizable target in cancer cells for antibody-drug conjugate development
Marquez J, Dong J, Dong C, Tian C, Serrero G (2021) Identification of prostaglandin F2 receptor negative regulator (PTGFRN) as an internalizable target in cancer cells for antibody-drug conjugate development. PLoS One 16(1):e0246197. doi: 10.1371/journal.pone.0246197
Summary: PTGFRN is a cell-surface protein that is upregulated in certain cancer types, including head and neck and, notably, pediatric medulloblastoma, an aggressive cancer with limited therapeutic options. With the selection of the mouse monoclonal antibody 33B7, the authors identified PTGFRN as a potential therapy target, and show that it is internalized by incubation with 33B7. Purified 33B7 antibody was sent to Advanced Targeting Systems where saporin was directly conjugated to the Fc region of 33B7 using their proprietary cleavable linker.
Usage: In a 96-well plate, 2000 cells/well were plated in triplicate in 100 μL of DMEM/F12 medium supplemented with 2.5% FBS, 0.4 ug/ml 33B7 antibody, and 0.9ug/ml of Fab-ZAP mouse. As an isotype control, cells were incubated with mouse Fab IgG-SAP as control (instead of 33B7) and Fab-ZAP.
Related Products: Fab-ZAP mouse (Cat. #IT-48), Fab IgG-SAP (Cat. #IT-67), Custom Conjugates
Efficacy and safety of anti-CD45-saporin as conditioning agent for RAG deficiency.
Castiello MC, Bosticardo M, Sacchetti N, Calzoni E, Fontana E, Yamazaki Y, Draghici E, Corsino C, Bortolomai I, Sereni L, Yu HH, Uva P, Palchaudhuri R, Scadden DT, Villa A, Notarangelo LD (2021) Efficacy and safety of anti-CD45-saporin as conditioning agent for RAG deficiency. J Allergy Clin Immunol 147(1):309-320.e6. doi: 10.1016/j.jaci.2020.04.033
Objective: To improve multi-lineage engraftment using non-genotoxic conditioning with Anti-CD45-Saporin.
Summary: Conditioning with Anti-CD45 antibody-drug conjugates may represent a novel and safe conditioning regimen for patients with RAG deficiency and other inborn errors of immunity.
Usage: Intravenous injection of Anti-CD45-SAP (3 mg/kg).
Related Products: Streptavidin-ZAP (Cat. #IT-27)
Pseudomonas Exotoxin A based toxins targeting epidermal growth factor receptor for the treatment of prostate cancer
Fischer A, Wolf I, Fuchs H, Masilamani AP, Wolf P (2020) Pseudomonas Exotoxin A based toxins targeting epidermal growth factor receptor for the treatment of prostate cancer. Toxins (Basel) 12(12):753. doi: 10.3390/toxins12120753
Summary: Refers to chimeric murine-human mAb cetuximab bound to Streptavidin-ZAP.
Related Products: Streptavidin-ZAP (Cat. #IT-27)
Cellular uptake of vitamin B12: Role and fate of TCblR/CD320, the transcobalamin receptor.
Gick GG, Arora K, Sequeira JM, Nakayama Y, Lai SC, Quadros EV (2020) Cellular uptake of vitamin B12: Role and fate of TCblR/CD320, the transcobalamin receptor. Exp Cell Res 396(1):112256. doi: 10.1016/j.yexcr.2020.112256
Summary: The increased and sustained expression of TCblR in proliferating cells has been used to target toxins preferentially to cancer cells and can be potentially used for targeted delivery of other anti-cancer drugs. In 2010 the authors published a paper which evaluated the potential of using immunotoxins to eliminate cancer cells expressing TCblR the authors performed a series of in vitro experiments using their monoclonal antibody plus Mab-ZAP in varying concentrations. The results indicated that this is a viable therapeutic model that causes minimal peripheral damage.
Related Products: Mab-ZAP (Cat. #IT-04)
The EphA2 and cancer connection: potential for immune-based interventions
London M, Gallo E (2020) The EphA2 and cancer connection: potential for immune-based interventions. Mol Biol Rep 47(10):8037-8048. doi: 10.1007/s11033-020-05767-y
Summary: The authors review the most current mAb-based therapies against EphA2-expressing cancers currently in pre-clinical and/or clinical stages. They reference Sakamoto et al. who performed in vitro testing of two different EphA2 mAbs mixed with Mab-ZAP to discover their therapeutic potential against melanoma.
Related Products: Mab-ZAP (Cat. #IT-04)
Antibody-drug conjugates targeting CD45 plus Janus kinase inhibitors effectively condition for allogeneic hematopoietic stem cell transplantation
Persaud SP, Ritchey JK, Choi J, Ruminski PG, Cooper ML, Rettig MP, DiPersio JF (2020) Antibody-drug conjugates targeting CD45 plus Janus kinase inhibitors effectively condition for allogeneic hematopoietic stem cell transplantation. bioRxiv 2020.10.02.324475. doi: 10.1101/2020.10.02.324475
Related Products: Streptavidin-ZAP (Cat. #IT-27), Blank-Streptavidin-SAP (Cat. #IT-27B)