scholarly journals Abstract 2954: Humanized CCR8 mouse model provides a translational tool for anti-human CCR8 antibody drug development

2021 ◽  
Author(s):  
Linlin Wang ◽  
Chengzhang Shang ◽  
Jing Zhang ◽  
Yichao Chen ◽  
Leila Kokabee ◽  
...  
Keyword(s):  
Mouse Model ◽  
Drug Development ◽  
Antibody Drug

Abstract 529: Characterization of a humanized TLR8 mouse model and its application in immuno-oncology drug development

2021 ◽  
Author(s):  
Hongjuan Zhang ◽  
Ruilin Sun ◽  
Annie X. An ◽  
Henry Q.x Li ◽  
Davy Xuesong Ouyang
Keyword(s):  
Mouse Model ◽  
Drug Development ◽  
Oncology Drug ◽  
Oncology Drug Development

scholarly journals A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open-Access Malaria Box

2018 ◽  
Vol 62 (4) ◽  
pp. e01505-17 ◽  
Author(s):  
R. S. Jumani ◽  
K. Bessoff ◽  
M. S. Love ◽  
P. Miller ◽  
E. E. Stebbins ◽  
...  
Keyword(s):  
Mouse Model ◽  
Drug Development ◽  
Early Stage ◽  
New Drugs ◽  
Cryptosporidium Hominis ◽  
Content Type ◽  
Knockout Mouse Model ◽  
Malaria Box

ABSTRACTCryptosporidiosis causes life-threatening diarrhea in children under the age of 5 years and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to the need for new drugs, better knowledge of drug properties that drivein vivoefficacy is needed to facilitate drug development. We report the identification of a piperazine-based lead compound forCryptosporidiumdrug development, MMV665917, and a new pharmacodynamic method used for its characterization. The identification of MMV665917 from the Medicines for Malaria Venture Malaria Box was followed by dose-response studies,in vitrotoxicity studies, and structure-activity relationship studies using commercial analogues. The potency of this compound againstCryptosporidium parvumIowa and field isolates was comparable to that againstCryptosporidium hominis. Furthermore, unlike nitazoxanide, clofazimine, and paromomycin, MMV665917 appeared to be curative in a NOD SCID gamma mouse model of chronic cryptosporidiosis. MMV665917 was also efficacious in a gamma interferon knockout mouse model of acute cryptosporidiosis. To determine if efficacy in this mouse model of chronic infection might relate to whether compounds are parasiticidal or parasitistatic forC. parvum, we developed a novelin vitroparasite persistence assay. This assay suggested that MMV665917 was parasiticidal, unlike nitazoxanide, clofazimine, and paromomycin. The assay also enabled determination of the concentration of the compound required to maximize the rate of parasite elimination. This time-kill assay can be used to prioritize early-stageCryptosporidiumdrug leads and may aid in planningin vivoefficacy experiments. Collectively, these results identify MMV665917 as a promising lead and establish a new method for characterizing potential anticryptosporidial agents.

DS-8201a, a HER2-targeting antibody-drug conjugate, to elicit immune responses and benefits in combination with an anti-PD-1 antibody.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1031-1031 ◽  
Author(s):  
Tomomi Nakayama Iwata ◽  
Chiaki Ishii ◽  
Yusuke Ogitani ◽  
Teiji Wada ◽  
Toshinori Agatsuma
Keyword(s):  
Mouse Model ◽  
Immune Responses ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Antitumor Efficacy ◽  
Class I ◽  
Antibody Drug Conjugate ◽  
Antitumor Effects ◽  
Drug Conjugate ◽  
Antibody Drug

1031 Background: DS-8201a, a HER2-targeting antibody–drug conjugate (ADC), with a topoisomerase I inhibitor, exatecan drivative (DX-8951 derivative, DXd) has been shown to have antitumor effects in preclinical xenograft models and clinical trials, but the involvement of the immune system in the antitumor efficacy of DS-8201a has not been elucidated yet. Methods: The antitumor efficacy of DS-8201a individually and in combination with an anti-PD-1 antibody was determined in a syngeneic mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Mice whose tumors had been cured by DS-8201a treatment were rechallenged with CT26.WT-hHER2 cells; their splenocytes were co-cultured with CT26.WT-hHER2 or CT26.WT-mock cells, and IFN-g secretion by these cells was determined. To investigate effects of DXd and DS-8201a on dendritic cells (DCs), the expression of DC markers on bone marrow derived DCs (BMDCs) and intratumoral DCs was analyzed by flow cytometry. Furthermore, MHC class I and PD-L1 expression on tumor cells was analyzed. Results: At a weekly dosage of 10 mg/kg, DS-8201a showed significant antitumor effects in the mouse model. Mice whose tumors had been cured by DS-8201a treatment rejected the rechallenge with CT26.WT-hHER2 cells, and splenocytes from these mice were activated by both CT26.WT-hHER2 and CT26.WT-mock cells. In the mouse model, DS-8201a treatment raised a population of intratumoral DCs (CD45+CD11c+MHC class II+) and increased DC expression of CD86, a DC activation marker; DXd also up-regulated CD86 expression on BMDCs in vitro. Furthermore, DS-8201a up-regulated PD-L1 and MHC class I expression on tumor cells. Notably, antitumor effects of the combination of DS-8201a with an anti-PD-1 antibody were better than those of monotherapy. Conclusions: DS-8201a elicits immune responses via mechanisms other than cytotoxic effects on tumor cells. This finding suggests additional benefits of combining DS-8201a with an immune checkpoint inhibitor (ICI). The combination of DS-8201a and an anti-PD-1 antibody was effective in tumor suppression, indicating that DS-8201a may be successfully combined with an ICI in human clinical applications.

scholarly journals Identification of genetic variants regulating the abundance of clinically relevant plasma proteins using the Diversity Outbred mouse model

2020 ◽  
Author(s):  
Stéphanie Philtjens ◽  
Dominic J. Acri ◽  
Byungwook Kim ◽  
Hyewon Kim ◽  
Jungsu Kim
Keyword(s):  
Quantitative Trait Loci ◽  
Mouse Model ◽  
Drug Development ◽  
Plasma Protein ◽  
Genetic Variants ◽  
Quantitative Trait ◽  
Plasma Proteins ◽  
Genetic Modifiers ◽  
Protein Levels ◽  
Diversity Outbred

AbstractAlthough there have been numerous expression quantitative trait loci (eQTL) studies, the effect of genetic variants on the levels of multiple plasma proteins still warrants more systematic investigation. To identify genetic modifiers that influence the levels of clinically relevant plasma proteins, we performed protein quantitative trait locus (pQTL) mapping on 92 proteins using the Diversity Outbred (DO) mouse population and identified 12 significant cis and 6 trans pQTL. Among them, we discovered coding variants in a cis-pQTL in Ahr and a trans-pQTL in Rfx1 for the IL-17A protein. Our study reports an innovative pipeline for the identification of genetic modifiers that may be targeted for drug development.Author SummaryBlood plasma is a body fluid that can be collected in a noninvasive way to detect diseases, such as autoimmune disease. However, it is known that plasma protein levels are affected by both the environment and genetic background. To determine the effect of genetics on plasma protein levels in human, one needs a rather large sample size. To overcome this critical issue, a mouse model, the Diversity Outbred (DO), was established that is genetically as diverse as the human population. In this study, we used N=140 DO mice and genotyped over 140,000 variants. In addition, we measured the levels of 92 proteins in plasma of these DO mice using Olink Proteomics technology. The proteins detected in this panel are known to be detectable in human plasma, making our study translatable to human. We identified 18 significant protein quantitative trait loci. Furthermore, we describe an analysis pipeline that allows for the detection of a single gene in the locus that is responsible for the differences in protein levels. We identified how variants in the Regulatory Factor X1 (Rfx1) gene regulates Interleukin-17A (IL-17A) plasma levels. Our study reports an innovative approach to identify genetic modifiers that may be targeted for drug development.

Improving antibody drug development using bionanotechnology

2022 ◽  
Vol 74 ◽  
pp. 137-145
Author(s):  
Emily K Makowski ◽  
John S Schardt ◽  
Peter M Tessier
Keyword(s):  
Drug Development ◽  
Antibody Drug
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