A5034251438- HER2/EGFR in Cancer Research
- Chronic Lymphocytic Leukemia Research
- Monoclonal and Polyclonal Antibodies Research
- Cancer therapeutics and mechanisms
- Synthesis and pharmacology of benzodiazepine derivatives
- Cancer Treatment and Pharmacology
- CAR-T cell therapy research
- Neuroblastoma Research and Treatments
- Lymphoma Diagnosis and Treatment
- Multiple Myeloma Research and Treatments
- Prostate Cancer Treatment and Research
- Protein Degradation and Inhibitors
- Nuclear Receptors and Signaling
- Radiopharmaceutical Chemistry and Applications
CRUK Lung Cancer Centre of Excellence
2024
University College London
2016-2024
Cancer Research UK
2018-2020
Spirogen (United Kingdom)
2016-2018
Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field antibody–drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One reactive imines capped a cathepsin B-cleavable valine-alanine linker. A robust synthetic route developed allow production tesirine on clinical scale, employing flexible, convergent strategy....
Abstract Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. dimer SG3199 is the released warhead component of antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. was potently cytotoxic against panel human solid tumour and haematological...
Abstract Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase that highly expressed in nearly all prostate cancers with the highest expression metastatic castration-resistant cancer (mCRPC). The prevalence of increased surface and constitutive internalization PSMA make it an attractive target for antibody–drug conjugate (ADC) approach to treating patients mCRPC. MEDI3726 (previously known as ADCT-401) ADC consisting engineered version anti-PSMA antibody...
Abstract Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas have poor patient outcomes; novel therapies are needed. CD22 is an attractive target for antibody–drug conjugates (ADCs), being highly expressed in R/R B-ALL with rapid internalization kinetics. ADCT-602 a CD22-targeting ADC, consisting of humanized mAb hLL2-C220, site specifically conjugated to the pyrrolobenzodiazepine dimer–based payload tesirine. In preclinical studies, demonstrated potent,...
Abstract Antibody–drug conjugates (ADC) containing pyrrolobenzodiazepine (PBD) dimers are being evaluated clinically in both hematologic and solid tumors. These include ADCT-301 (camidanlumab tesirine) ADCT-402 (loncastuximab pivotal phase II trials that contain the payload tesirine, which releases PBD dimer warhead SG3199. An important consideration future clinical development is acquired resistance. The aim was to generate characterize resistant cell lines tumor settings. Human Karpas-299...
Abstract ADCT-502 is an ADC composed of engineered version humanized IgG1 trastuzumab, directed against human HER2, site-specifically conjugated to the highly cytotoxic PBD-based linker-drug tesirine (drug-antibody ratio 1.7). In vitro, has potent and targeted cytotoxicity various solid cancer cell lines. vivo, demonstrates strong durable antitumor activity in mouse xenografts with levels but inactive a HER2-negative xenograft. stable, well tolerated favorable PK profile both rat cynomolgus...
<p>Supplementary Fig. S1. Structure and characterization of ADCT-602. (A) Full-length amino acid sequence light heavy chains hLL2-C220, with the mutations C219S in chain C225V C228V indicated bold. (B) ADCT-602 PBD dimer payload tesirine (SG3249) conjugated at C219 hLL2-CC20 (C220 according to EU numbering system) chain. (C) characterized by size exclusion chromatography (D) reduced reversed-phase chromatography. L indicates elution chain, whereas H0 H1 indicate unconjugated H-chain or...
<div>Abstract<p>Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas have poor patient outcomes; novel therapies are needed. CD22 is an attractive target for antibody–drug conjugates (ADCs), being highly expressed in R/R B-ALL with rapid internalization kinetics. ADCT-602 a CD22-targeting ADC, consisting of humanized mAb hLL2-C220, site specifically conjugated to the pyrrolobenzodiazepine dimer–based payload tesirine. In preclinical studies,...
<div>Abstract<p>Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas have poor patient outcomes; novel therapies are needed. CD22 is an attractive target for antibody–drug conjugates (ADCs), being highly expressed in R/R B-ALL with rapid internalization kinetics. ADCT-602 a CD22-targeting ADC, consisting of humanized mAb hLL2-C220, site specifically conjugated to the pyrrolobenzodiazepine dimer–based payload tesirine. In preclinical studies,...
<p>Supplementary File. Supervised analyses in B-cell lymphoma cell lines using Illumina HT-12 microarray data This file contains all data, as well lists of transcripts upregulated (logFC+) or downregulated (logFC−) the resistant lines, gene sets significantly enriched 2 groups and IRAK1 expression levels from microarray.</p>
<p>Supplementary Fig. S3. Confocal microscopy images of Ramos cells treated with B12-C220-SG3249 and stained for nuclei (blue), LAMP-1 (red), human IgG antibody (green).</p>
<p>Supplementary Fig. S9. In vitro cytotoxicity of B12-C220-SG3249 following pretreatment with chidamide for 7 days (Ramos, TMD8, and SU-DHL-4 cell lines).</p>
<p>Supplementary Fig. S2. The in vitro antitumor activity of ADCT-602 does not correlate with CD22 levels B-cell lymphomas. This figure shows a correlation IC50 values versus (A) cell surface protein expression via absolute fluorescence quantitation Quantum Simply Cellular microspheres, (B) RNA measured Illumina HT-12 microarrays, and (C) targeted RNA-Seq the HTG EdgeSeq Oncology Biomarker Panel. On each plot, x-axes are presented as log2, y-axes log2. Cell lines derived from Hodgkin...
<p>Supplementary Fig. S5. Kaplan–Meier survival analysis in (A) Ramos and (B) WSU-DLCL2 xenograft models. plots showing percentage animal over 60 days xenograft; 59 cancer xenograft. QD once daily.</p>
<p>Supplementary Fig. S8. Quantification of cynomolgus monkey CD3+, platelets, reticulocytes, and neutrophils after dosing ADCT-602 at 0.6 or 0.9 mg/kg (2 doses, 21 days apart). Data presented as mean ± SEM (each group, n = 3). standard error mean.</p>
<p>Supplementary Fig. S3. Confocal microscopy images of Ramos cells treated with B12-C220-SG3249 and stained for nuclei (blue), LAMP-1 (red), human IgG antibody (green).</p>
<p>Supplementary Fig. S1. Structure and characterization of ADCT-602. (A) Full-length amino acid sequence light heavy chains hLL2-C220, with the mutations C219S in chain C225V C228V indicated bold. (B) ADCT-602 PBD dimer payload tesirine (SG3249) conjugated at C219 hLL2-CC20 (C220 according to EU numbering system) chain. (C) characterized by size exclusion chromatography (D) reduced reversed-phase chromatography. L indicates elution chain, whereas H0 H1 indicate unconjugated H-chain or...
<p>Supplementary File. Supervised analyses in B-cell lymphoma cell lines using Illumina HT-12 microarray data This file contains all data, as well lists of transcripts upregulated (logFC+) or downregulated (logFC−) the resistant lines, gene sets significantly enriched 2 groups and IRAK1 expression levels from microarray.</p>
<p>Supplementary Fig. S4. Time course of DNA ICL formation in KARPAS-299 cells following a 2-hour treatment with ADCT-602 or SG3199. Results are presented as mean percentage decrease OTM ± SD (n = 4). interstrand crosslinking; Olive tail moment.</p>
<p>Supplementary Fig. S8. Quantification of cynomolgus monkey CD3+, platelets, reticulocytes, and neutrophils after dosing ADCT-602 at 0.6 or 0.9 mg/kg (2 doses, 21 days apart). Data presented as mean ± SEM (each group, n = 3). standard error mean.</p>
<p>Supplementary Fig. S9. In vitro cytotoxicity of B12-C220-SG3249 following pretreatment with chidamide for 7 days (Ramos, TMD8, and SU-DHL-4 cell lines).</p>