A5087586287- Monoclonal and Polyclonal Antibodies Research
- Chronic Lymphocytic Leukemia Research
- CAR-T cell therapy research
- Lymphoma Diagnosis and Treatment
- Immunotherapy and Immune Responses
- T-cell and B-cell Immunology
- Cancer Immunotherapy and Biomarkers
- Glycosylation and Glycoproteins Research
- Immune Cell Function and Interaction
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- Cancer Research and Treatments
- DNA and Nucleic Acid Chemistry
- Orthopaedic implants and arthroplasty
- Nanofabrication and Lithography Techniques
- Tissue Engineering and Regenerative Medicine
- Cancer, Lipids, and Metabolism
- Radiopharmaceutical Chemistry and Applications
- Diabetes and associated disorders
- Chemical Reactions and Isotopes
- Single-cell and spatial transcriptomics
- Dental Implant Techniques and Outcomes
- Pluripotent Stem Cells Research
- Complement system in diseases
- Multiple Myeloma Research and Treatments
Genmab (Netherlands)
2011-2024
Leiden University Medical Center
2018
Genmab (United States)
2012-2015
University of California, Santa Barbara
2004
Bronkhorst (Netherlands)
2003
IgG antibodies can organize into ordered hexamers on cell surfaces after binding their antigen. These bind the first component of complement C1 inducing complement-dependent target killing. Here, we translated this natural concept a novel technology platform (HexaBody technology) for therapeutic antibody potentiation. We identified mutations that enhanced hexamer formation and activation by IgG1 against range targets cells from hematological solid tumor indications. backbones with preferred...
The novel Bruton tyrosine kinase inhibitor ibrutinib and phosphatidyl-4-5-biphosphate 3-kinase-δ idelalisib are promising drugs for the treatment of chronic lymphocytic leukemia B-cell non-Hodgkin lymphoma, either alone or in combination with anti-CD20 antibodies. We investigated possible positive negative impact these on all known mechanisms action both type I II Pretreatment 1 hour did not increase direct cell death lines samples mediated by Pre-treatment inhibit complement activation...
We previously reported that 1 h after infusion of CD20 mAb rituximab in patients with chronic lymphocytic leukemia (CLL), >80% was removed from circulating B cells, and we replicated this finding, based on vitro models. This reaction occurs via an endocytic process called shaving/trogocytosis, mediated by FcγR acceptor cells including monocytes/macrophages, which remove internalize rituximab-CD20 immune complexes cells. Beers et al. mAb-induced antigenic modulation as a result...
The CD20 mAb ofatumumab (OFA) induces complement-mediated lysis of B cells. In an investigator-initiated phase II trial OFA plus chemotherapy for chronic lymphocytic leukemia (CLL), treatment promoted partial CLL cell depletion that coincided with reduced complement titers. Remaining cells circulated bound and covalently breakdown product C3d, indicative ongoing activation. Presumably, neither complement- nor effector cell-based mechanisms were sufficiently robust to clear these remaining...
BackgroundDuoBody®-CD3xCD20 (GEN3013) is a full-length human IgG1 bispecific antibody (bsAb) recognizing CD3 and CD20, generated by controlled Fab-arm exchange. Its Fc domain was silenced introduction of mutations L234F L235E D265A.MethodsT-cell activation T-cell-mediated cytotoxicity were measured flow cytometry following co-culture with tumour cells. Anti-tumour activity DuoBody-CD3xCD20 assessed in humanized mouse models vivo. Non-clinical safety studies performed cynomolgus...
Background Rituximab is used in the treatment of CD20+ B cell lymphomas and other lymphoproliferative disorders. Its clinical efficacy might be further improved by combinations with drugs such as statins that inhibit cholesterol synthesis show promising antilymphoma effects. The objective this study was to evaluate influence on rituximab-induced killing lymphomas. Methods Findings Complement-dependent cytotoxicity (CDC) assessed MTT Alamar blue assays well trypan staining, antibody-dependent...
Human IgG is produced with C-terminal lysines that are cleaved off in circulation. The function of this modification was unknown and generally thought not to affect antibody function. We recently reported efficient C1q binding complement-dependent cytotoxicity (CDC) requires hexamerization at the cell surface. Here we demonstrate may interfere process, leading suboptimal CDC cells opsonized lysine-containing IgG. After removed these a carboxypeptidase, maximal complement activation observed....
Bispecific antibodies (bsAbs) bridging CD3 on T-cells to tumor-associated antigens (TAA) tumor cells can direct T-cell immunity solid tumors. "Bystander killing", where targeting of TAA-positive also leads the eradication TAA-negative cells, may overcome TAA heterogeneity. While bystander activity activated, engineered has been shown be robust and wide-reaching, spatiotemporal aspects bsAb-mediated are unresolved. Here, we developed a model breast cancer tumoroids varying in HER2 expression...
Abstract Human IgG1 type I CD20 Abs, such as rituximab and ofatumumab (OFA), efficiently induce complement-dependent cytotoxicity (CDC) of CD20+ B cells by binding C1 to hexamerized Fc domains. Unexpectedly, we found that Ab F(ab′)2 fragments, well C1q-binding–deficient IgG mutants, retained an ability CDC, albeit with lower efficiency than for whole or unmodified IgG. Experiments using human serum depleted specific complement components demonstrated the observed lytic activity, which termed...
Abstract The mechanism of action bispecific antibodies (bsAbs) directing T-cell immunity to solid tumors is incompletely understood. Here, we screened a series CD3xHER2 bsAbs using extracellular matrix (ECM) embedded breast cancer tumoroid arrays exposed healthy donor-derived T-cells. An initial phase random movement throughout the ECM (day 1–2), was followed by bsAb-dependent active recruitment tumoroids 2–4), and killing 4–6). Low affinity HER2 or CD3 arms were compensated for increasing...
<h3>Background</h3> γδT cells have emerged as a promising candidate for cancer immunotherapy due to major histocompatibility complex (MHC) independence, epithelial tissue residency and cytotoxic activity.<sup>1</sup> cell receptors undergo V(D)J recombination similarly αβT. Single studies show distinct functional temporal properties based on variable gene usage; the most abundant subtypes are Vδ1 Vδ2.<sup>2 3</sup> Demonstrating posited mechanism of anti-tumor in formalin fixed paraffin...
In the present study, we tested in vitro process of differentiation and mineralization as well vivo bone formation on substrates with different macrostructures. We used carbonated apatite-coated titanium discs that were respectively smooth, plasma spayed or had a porous structure. Subcultured rat marrow cells seeded after 7 days culture, tissue-coated subcutaneously implanted nude mice for 4 weeks. After 1 week culture presence osteogenic promoter dexamethasone, formed continuous layer...
CD3 bispecific antibodies (bsAbs) show great promise as anticancer therapeutics. Here, we in-depth mechanistic studies of a bsAb in solid cancer, using DuoBody-CD3x5T4. Cross-linking T cells with tumor expressing the oncofetal antigen 5T4 was required to induce cytotoxicity. Naive and memory CD4+ CD8+ were equally effective at mediating cytotoxicity, DuoBody-CD3x5T4 induced partial differentiation naive T-cell subsets into memory-like cells. Tumor cell kill associated activation,...