A5025114625- Toxin Mechanisms and Immunotoxins
- Glycosylation and Glycoproteins Research
- Monoclonal and Polyclonal Antibodies Research
- Galectins and Cancer Biology
- Silymarin and Mushroom Poisoning
- Multiple Myeloma Research and Treatments
- Radiopharmaceutical Chemistry and Applications
- Protist diversity and phylogeny
- Virus-based gene therapy research
- HER2/EGFR in Cancer Research
- Microbial Community Ecology and Physiology
- Flavonoids in Medical Research
- Animal Disease Management and Epidemiology
- Virology and Viral Diseases
- HIV Research and Treatment
- Cell Adhesion Molecules Research
- Methane Hydrates and Related Phenomena
- Mass Spectrometry Techniques and Applications
- Peptidase Inhibition and Analysis
- Fungal Biology and Applications
- RNA Interference and Gene Delivery
- CAR-T cell therapy research
- Photosynthetic Processes and Mechanisms
- Nanoparticle-Based Drug Delivery
- Advanced Proteomics Techniques and Applications
Heidelberg Pharma (Germany)
2015-2024
Max Planck Institut für Zellbiologie
2019
German Cancer Research Center
2009-2015
Heidelberg University
2009-2013
Technical University of Darmstadt
2005-2011
Despite major treatment advances in recent years, patients with multiple myeloma inevitably relapse. The RNA polymerase II complex has been identified as a promising therapeutic target both proliferating and dormant cancer cells. Alpha-amanitin, toxin so far without clinical application due to high liver toxicity, specifically inhibits this complex. Here, we describe the development of HDP-101, an anti-B-cell maturation antigen (BCMA) antibody conjugated amanitin derivative. HDP-101...
Abstract Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels the target on surface cancer have potential restore efficacy immunotherapy. Here, we use our CRISPR interference– and activation–based functional genomics platform systematically identify pathways controlling cell expression multiple myeloma B-cell maturation (BCMA). We discovered pharmacologic inhibition HDAC7 Sec61 complex increased BCMA, including...
<p>Dose of hRS7 ATAC 1 and 2 with indicated dose α-amanitin used in BxPC-3 Capan-1 dose-response efficacy studies.</p>
<p>MS spectra of DAR determination. Western blotting TROP2 expression on PDAC cell lines. Internalization antibody in In vitro cytotoxicity ADCs MTD and efficacy studies. Spiderplot animals treated with ADCs.</p>
<p>Internalization of hRS7-LALA-DC antibody in PDAC cell lines. Flow cytometry gating was performed according to the PANC-1 cells that do not express TROP2.</p>
<p><i>In </i><i>vivo</i> antitumor efficacy of individual animals treated with Trodelvy compared to hRS7 ATAC 1 in TNBC xenograft mouse model. Female NMRI nude mice bearing HCC70 subcutaneous tumors were either PBS or the indicated doses (cleavable linker) Trodelvy. Efficacy was monitored for 76 days and evaluated by average tumor volume ±SEM, n = 10.</p>
<p>Western blotting of TROP2 expression on PANC-1, BxPC-3, Capan-1 and Capan-2 cells. hRS7-LALA-DC was used as primary antibody rabbit anti-human-IgG-HRP (Abcam) secondary antibody. Chemiluminescence signal detected by WB imager (Azure C400 imaging). The different apparent size TROP-2 in BxPC3 Capan 2 cells is most likely due to differential glycosylation [44] and/or from proteolytic cleavage [45]. In not detected, proteolytical resulting an isoform that cannot be the hRS7 [45], [46].</p>
<p>Deconvoluted MS spectra for hRS7 ATAC 1 (A) and (B) conjugates. The drug-to-antibody (DAR) ratio was measured using intact LC-MS analysis.</p>
<p>a. In vitro cytotoxicity of hRS7 ATAC 1 in tumor cells with medium (A; NCI-N87 cells) and low TROP-2 expression (B; MCF-7 b. PDAC upon transient acidosis or acid adaptation. BxPC-3 (TROP2+++) Capan-1 (TROP2++) were incubated at normal pH 6.6 for 24 hours, 7 days month then treated 96 hours 1. c. Trodelvy TNBC d. <i>In vitro</i> compared to cells.</p>
<p>MTD of hRS7 ATAC 1 and 2. The tolerability was assessed in 7-week-old tumor free female NMRI nude mice by single dose intravenous administration ATACs. At a 10 mg/kg 1, one three animals found dead within 48 h after treatment thus 8 considered to be MTD. ATAC2 tested up maximum 80 – no higher doses were tested. Therefore, the MTD ≥ mg/kg.</p>
<div>Abstract<p>Trophoblast cell surface antigen 2 (TROP2) exhibits aberrant expression in pancreatic cancer, correlating with metastasis, advanced tumor stage, and poor prognosis patients ductal adenocarcinoma. TROP2 has been recognized as a promising therapeutic target for antibody–drug conjugates (ADC), evidenced by the approval of anti-TROP2 ADC Trodelvy treatment triple-negative breast cancer (TNBC). In this study, we report generation novel second-generation amanitin-based...
<p>Supplementary Table 2 shows the 6226 human plasma membrane and secreted proteins screened</p>
<p>Supplementary Figure 6 shows the analysis of nectin-4 expression in TNBC</p>
<p>Supplementary Table 6 shows the summary of GLP toxicology study results </p>
<p>Supplementary Table 3 shows the affinities (Octet) of anti-hnectin-4 mAbs for monomeric and dimeric human nectin-4 </p>
<p>Supplementary Table 5 shows the analysis of average Drug Antibody Ratio in monkey plasma </p>
<p>Supplementary Figure 2 shows IHC analysis of Nectin-4 expression on tumor tissue and human skin keratinocytes using 15A7.5</p>
<p>Supplementary Figure 3 shows the internalization of 15A7.5 and Ha22</p>
<p>Supplementary Figure 5 shows IHC analysis of ETx-22 infiltration and pharmacodynamic in SUM190PT tumors</p>
<p>Supplementary Figure 4 shows the analysis of ETx-22 infiltration in SUM190PT tumors</p>
<p>Supplementary Figure 1 shows epitope mapping of humanized 15A7.5 to human nectin-4</p>
<p>Supplementary Table 1 shows apparent affinity of various chimeric mAbs and human HA22 anti-nectin-4 mAbs</p>
<p>Supplementary Table 4 shows the PK data of ETx-22 in Cynomolgus monkeys</p>