المؤلفون: Andrey Kulikov, Elena Shipaeva, Anastasia Dmitrieva, Vera Batrak, Georgy Shipunov, Colin Guy, Jill Smith, Ran Zhang, Michael Zhang, Jeff Duan, Anton Chestukhin, Sergei Barbashov, Mikhail Samsonov, Yan Lavrovsky

المصدر: Frontiers in Pharmacology, Vol 12 (2021)

مصطلحات موضوعية: cancer immunotherapy, monoclonal antibody, PD-L1, in vitro efficacy, animal models, therapeutic agent, Therapeutics. Pharmacology, RM1-950

الوصف: RPH-120 is a novel fully human anti-PD-L1 IgG1 monoclonal antibody with specifically designed Asn300Ala mutation in Fc fragment. Surface plasmon resonance assay showed that affinity of the RPH-120 to the dimeric form of human PD-L1-Fc fusion protein was much higher than affinity to the monomeric His-tagged PD-L1. Further binding studies demonstrated that RPH-120 is able to bind to human and monkey but not mouse PD-L1. Tissue cross-reactivity study showed good comparability of human and Cynomolgus monkeys tissue staining. Bioactivity was assessed using mixed lymphocyte reaction assay. This study revealed that RPH-120 was able to activate T cells preventing PD1/PD-L1 interaction. Antitumor efficacy was analyzed in HCC-827 lung cancer xenografts in humanized CD34+ mice at three dosage levels: 20, 80, and 200 mg/kg. RPH-120 demonstrated significant tumor growth inhibition, and this inhibition was comparable to that of atezolizumab. In a single dose toxicity, toxicokinetic and dose range finding study performed in Cynomolgus monkeys, RPH-120 was administered via intravenous (IV) bolus or 60-min IV infusion, followed by 8-weeks recovery period. An acceptable toxicokinetic profile was demonstrated and administration at doses of up to 200 mg/kg was well tolerated by all animals. In conclusion, RPH-120 revealed promising in vitro and in vivo activity and safety. RPH-120 is a potent anti-PD-L1 drug candidate for cancer immunotherapy.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fphar.2021.723038/fullTest; https://doaj.org/toc/1663-9812Test

الوصول الحر: https://doaj.org/article/5dbb2234d8f24276a1a0965cf6215e2eTest

المؤلفون: Artem Blagodatski, Vera Batrak, Sabine Schmidl, Ulrike Schoetz, Randolph B Caldwell, Hiroshi Arakawa, Jean-Marie Buerstedde

المصدر: PLoS Genetics, Vol 5, Iss 1, p e1000332 (2009)

مصطلحات موضوعية: Genetics, QH426-470

الوصف: Hypermutation of the immunoglobulin (Ig) genes requires Activation Induced cytidine Deaminase (AID) and transcription, but it remains unclear why other transcribed genes of B cells do not mutate. We describe a reporter transgene crippled by hypermutation when inserted into or near the Ig light chain (IgL) locus of the DT40 B cell line yet stably expressed when inserted into other chromosomal positions. Step-wise deletions of the IgL locus revealed that a sequence extending for 9.8 kilobases downstream of the IgL transcription start site confers the hypermutation activity. This sequence, named DIVAC for diversification activator, efficiently activates hypermutation when inserted at non-Ig loci. The results significantly extend previously reported findings on AID-mediated gene diversification. They show by both deletion and insertion analyses that cis-acting sequences predispose neighboring transcription units to hypermutation.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC2607555?pdf=renderTest; https://doaj.org/toc/1553-7390Test; https://doaj.org/toc/1553-7404Test

الوصول الحر: https://doaj.org/article/079156d0041a4c42acafaec995b75adaTest

المؤلفون: Artem Blagodatski, Vera Batrak, Sabine Schmidl, Ulrike Schoetz, Olph B. Caldwell, Jean-marie Buerstedde

المساهمون: The Pennsylvania State University CiteSeerX Archives

المصدر: ftp://ftp.ncbi.nlm.nih.gov/pub/pmc/44/ce/PLoS_Genet_2009_Jan_9_5(1)_e1000332.tar.gz

مصطلحات موضوعية: These authors contributed equally to this work

الوصف: Hypermutation of the immunoglobulin (Ig) genes requires Activation Induced cytidine Deaminase (AID) and transcription, but it remains unclear why other transcribed genes of B cells do not mutate. We describe a reporter transgene crippled by hypermutation when inserted into or near the Ig light chain (IgL) locus of the DT40 B cell line yet stably expressed when inserted into other chromosomal positions. Step-wise deletions of the IgL locus revealed that a sequence extending for 9.8 kilobases downstream of the IgL transcription start site confers the hypermutation activity. This sequence, named DIVAC for diversification activator, efficiently activates hypermutation when inserted at non-Ig loci. The results significantly extend previously reported findings on AID-mediated gene diversification. They show by both deletion and insertion analyses that

وصف الملف: application/zip

العلاقة: http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.358.6977Test

المؤلفون: Hiroshi Arakawa, Hiroaki Kudo, Vera Batrak, Olph B. Caldwell, Michael A. Rieger, Joachim W. Ellwart, Jean-marie Buerstedde

المساهمون: The Pennsylvania State University CiteSeerX Archives

المصدر: http://nar.oxfordjournals.org/content/36/1/e1.full-text-lowres.pdfTest.

الوصف: in the B cell line DT40

وصف الملف: application/pdf

العلاقة: http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.554.8280Test; http://nar.oxfordjournals.org/content/36/1/e1.full-text-lowres.pdfTest

الإتاحة: http://nar.oxfordjournals.org/content/36/1/e1.full-text-lowres.pdfTest