A5087405110- Immunotherapy and Immune Responses
- Immune Response and Inflammation
- Chemical Synthesis and Analysis
- Radiopharmaceutical Chemistry and Applications
- Monoclonal and Polyclonal Antibodies Research
- Cancer Immunotherapy and Biomarkers
- Immune Cell Function and Interaction
- Click Chemistry and Applications
- Glycosylation and Glycoproteins Research
- Influenza Virus Research Studies
- Synthesis of β-Lactam Compounds
- vaccines and immunoinformatics approaches
- Cervical Cancer and HPV Research
- Hepatitis B Virus Studies
- Antimicrobial Peptides and Activities
- Complement system in diseases
- Synthesis and Biological Evaluation
- Neuroendocrine Tumor Research Advances
- Viral Infections and Outbreaks Research
- Pancreatic and Hepatic Oncology Research
- CAR-T cell therapy research
- Lung Cancer Treatments and Mutations
- HER2/EGFR in Cancer Research
- Hepatitis C virus research
- RNA Interference and Gene Delivery
Genmab (Netherlands)
2019-2024
Leiden University
2012-2023
Leiden University Medical Center
2014-2022
ISA Pharmaceuticals (Netherlands)
2017-2020
Abstract CD3 bispecific antibody (CD3 bsAb) therapy is clinically approved for refractory hematological malignancies, but responses in solid tumors have been limited so far. One of the main hurdles lack sufficient T-cell infiltrate. Here, we show that pre-treatment vaccination, even when composed tumor-unrelated antigens, induces CXCR3-mediated influx immunologically ‘cold’ tumor models male mice. In absence bsAb, infiltrate confined to invasive margin, whereas subsequent bsAb administration...
Abstract Chemical conjugates comprising synthetic Toll-like receptor ligands (TLR-L) covalently bound to antigenic long peptides (SLP) are attractive vaccine modalities, which can induce robust CD8+ T-cell immune responses. Previously, we have shown that the mechanism underlying power of TLR-L SLP is improved delivery antigen together with a dendritic cell activation signal. In present study, expanded approach tumor-specific CD4+ as well responses and in vivo studies two nonrelated...
Ligands for the Toll-like receptor (TLR) family can induce activation of cells innate immune system and are widely studied their potential to enhance adaptive immunity. Conjugation TLR2-ligand Pam3CSK4 synthetic long peptides (SLPs) was shown strongly induction antitumor To further improve cancer vaccination, we have previously that novel TLR2-L Amplivant (AV), a modified Pam3CSK4, potentiates maturation effects on murine DCs. In current study, assessed immunological properties AV.Naïve mice...
Targeted therapies and immunotherapy have shown promise in patients with non-small cell lung cancer (NSCLC). However, the majority of fail or become resistant to treatment, emphasizing need for novel treatments. In this study, we confirm prognostic value levels AXL, a member TAM receptor tyrosine kinase family, NSCLC demonstrate potent antitumor activity AXL-targeting antibody-drug conjugate enapotamab vedotin across different subtypes mouse clinical trial human NSCLC. Tumor regression...
Abstract The use of therapeutic monoclonal antibodies is constrained because single antigen targets often do not provide sufficient selectivity to distinguish diseased from healthy tissues. We present HexElect ® , an approach enhance the functional by making their activity dependent on clustering after binding two different antigens expressed same target cell. lmmunoglobulin G (lgG)-mediated membrane receptors naturally occurs cell surfaces trigger complement- or cell-mediated effector...
The potency of human papillomavirus type 16 (HPV16)-encoded synthetic long peptides (SLP), conjugated to an optimized Toll-like receptor 2 ligand (TLR2-L), was assessed in ex vivo activation HPV16+ cancer patient-derived T cells. Two highly immunogenic SLP sequences derived from the oncogenic E6 protein HPV16 were selected and a Pam3CSK4-based TLR2-L under GMP conditions. Both conjugates able mature DCs vitro activate skin-derived antigen-presenting cells (APCs) upon intradermal injection...
Background Amplivant is a molecularly optimized Toll-like receptor 2 ligand that can be covalently conjugated to tumor peptide antigens. In preclinical models, amplivant-adjuvanted synthetic long peptides (SLPs) strongly enhanced antigen presentation by dendritic cells, T cell priming and induction of effective antitumor responses. The current study first-in-human trial investigate safety immunogenicity amplivant human papillomavirus (HPV) 16-SLP. Methods A dose escalation phase I...
New analogues (UPam) of triacylated lipopeptide Pam3CysSK4, a popular agonist Toll-like receptor 2 (TLR2), were designed making use the cocrystal structure TLR2 heterodimer (with TLR1) with Pam3CysSK4. Twenty-two UPam derivatives that feature an N-tetradecylcarbamyl chain to mimic native N-palmitoyl moiety and various small amino acids residues at penultimate N-terminal position prepared via solid-phase synthesis. In vitro evaluation immunostimulatory properties revealed new potent ligands.
Simultaneous triggering of Toll-like receptors (TLRs) and NOD-like (NLRs) has previously been shown to synergistically activate monocytes, dendritic cells, macrophages. We applied these properties in a T-cell vaccine setting by conjugating the NOD2-ligand muramyl-dipeptide (MDP) TLR2-ligand Pam3CSK4 synthetic peptide derived from model antigen. Stimulation human DCs with MDP-peptide-Pam3CSK4 conjugate led strongly increased secretion pro-inflammatory Th1-type cytokines chemokines. further...
Muramyl dipeptide (MDP) is the smallest peptidoglycan fragment capable of triggering innate immune system through interaction with intracellular NOD2 receptor. To develop synthetic vaccine modalities composed an antigenic entity (typically a small peptide) and molecular adjuvant well-defined activity, we previously assembled covalent MDP-antigen conjugates. Although these were found to be stimulating receptor processed by dendritic cells (DCs) leading effective antigen presentation, DC...
Vaccination with synthetic long peptides (SLP) is a promising new treatment strategy for chronic hepatitis B virus (CHB). SLP can induce broad T-cell responses all HLA types. Here we investigated the ability of prototype HBV-core (HBc)-sequence-derived to boost HBV-specific T cells in CHB patients ex vivo.HBc-SLP was used assess cross-presentation by monocyte-derived dendritic (moDC) and BDCA1+ blood myeloid DC (mDC) engineered CD8+ cells. Autologous SLP-loaded toll-like receptor...
Synthetic long peptide (SLP) vaccination is a promising new treatment strategy for patients with chronic hepatitis B virus (HBV) infection. We have previously shown that prototype HBV-core protein derived SLP was capable of boosting CD4+ and CD8+ T cell responses in the presence TLR2-ligand HBV ex vivo. For optimal efficacy therapeutic vaccine vivo, adjuvants can be conjugated to ensure delivery both antigen co-stimulatory signal same antigen-presenting (APC). Dendritic cells (DCs) express...
Aiming to increase the potency of synthetic long peptide (SLP)-based cancer vaccines, Toll-like receptor 2 (TLR2) ligand Pam3CSK4 was conjugated in a chemically defined fashion SLPs harbouring both cytotoxic T lymphocyte (CTL) and helper epitopes. We recently showed that these SLP-conjugates induce strong antitumor immunity murine models.
The covalent attachment of an innate immune system stimulating agent to antigen can provide active vaccine modalities capable eliciting a potent response against the incorporated antigen. Here we describe design, automated synthesis and immunological evaluation set four muramyl dipeptide-peptide conjugates. Muramyl dipeptide (MDP) represents well-known ligand for intracellular NOD2 receptor our study shows that covalently linking MDP-moiety antigenic peptide lead construct is if attached at...
2614 Background: Therapeutic vaccines based on synthetic long peptides (SLPs) have a great potential for immunotherapy of cancer patients as these SLPs include both human leukocyte antigen (HLA) class I and II epitopes no patient selection HLA types is required. The antigen-induced immune response can be strengthened with stimulating additives. Amplivant (AV) Toll-like receptor 2 ligand which directly conjugated to tumor peptide antigens. In preclinical studies, AV-conjugation antigens led...
<p>PDF file - 266K, Supplementary figure 1. DC maturation by TLR2-L SLP conjugates.</p>
<p>PDF file - 679K, Supplementary figure 2. In vitro T-cell activation induced by conjugated SLP.</p>
<p>PDF file - 89K</p>
<div>Abstract<p>Chemical conjugates comprising synthetic Toll-like receptor ligands (TLR-L) covalently bound to antigenic long peptides (SLP) are attractive vaccine modalities, which can induce robust CD8<sup>+</sup> T-cell immune responses. Previously, we have shown that the mechanism underlying power of TLR-L SLP is improved delivery antigen together with a dendritic cell activation signal. In present study, expanded approach tumor-specific...
<p>PDF file - 89K</p>
<p>PDF file - 679K, Supplementary figure 2. In vitro T-cell activation induced by conjugated SLP.</p>
<p>PDF file - 266K, Supplementary figure 1. DC maturation by TLR2-L SLP conjugates.</p>
Clustering of the costimulatory TNF receptor superfamily member OX40 on activated T cells activates signaling pathways that enhance T-cell activation, survival, and proliferation. agonists in development requiring FcγR-mediated crosslinking to induce agonism have demonstrated limited clinical activity. We present preclinical characterization HexaBody-OX40 (GEN1055/BNT315), a novel agonist antibody designed cluster independent antitumor responses. Target binding characteristics agonistic...