Pretargeting of internalizing trastuzumab and cetuximab with a 18F-tetrazine tracer in xenograft models

Pretargeting-based approaches are being investigated for radioimmunoimaging and therapy applications to reduce the effective radiation burden to the patient. To date, only a few studies have used short-lived radioisotopes for pretargeting of antibodies, and such examples with internalizing antibodies are even rarer. Herein, we have investigated pretargeting methodology using inverse electron-demand Diels-Alder (IEDDA) for tracing two clinically relevant, internalizing monoclonal antibodies, cetuximab and trastuzumab. Bioorthogonal reaction between tetrazine and trans-cyclooctene (TCO) was used for tracing cetuximab and trastuzumab in vivo with a fluorine-18 (t (A 1/2) = 109.8 min) labelled tracer. TCO-cetuximab or TCO-trastuzumab was administered 24, 48, or 72 h prior to the injection of tracer to A431 or BT-474 tumour-bearing mice, respectively. With cetuximab, the highest tumour-to-blood ratios were achieved when the lag time between antibody and tracer injections was 72 h. With trastuzumab, no difference was observed between different lag times. For both antibodies, the tumour could be clearly visualized in the PET images with the highest tumour uptake of 3.7 +/- 0.1%ID/g for cetuximab and 1.5 +/- 0.1%ID/g for trastuzumab as quantified by ex vivo biodistribution. In vivo IEDDA reaction was observed in the blood for both antibodies, but with trastuzumab, this was to a much lower degree than with cetuximab. We could successfully visualize the tumours by using cetuximab and trastuzumab in pretargeted PET imaging despite the challenging circumstances where the antibody is internalized and there is still some unbound antibody circulating in the blood flow. This clearly demonstrates the potential of a pretargeted approach for targeting internalizing antigens and warrants development of pharmacokinetic optimization of the biorthogonal reactants to this end.Peer reviewe

Global prevalence and genotype distribution of hepatitis C virus infection in 2015 : A modelling study

Publisher Copyright: © 2017 Elsevier LtdBackground The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of—and expansion on—the 2014 analysis, which reported 80 million (95% CI 64–103) viraemic infections in 2013. Methods We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Findings Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1·0% (95% uncertainty interval 0·8–1·1) in 2015, corresponding to 71·1 million (62·5–79·4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). Interpretation The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections. Funding John C Martin Foundation.publishersversionPeer reviewe

Click-Mediated Pretargeted Radioimmunotherapy of Colorectal Carcinoma

Pretargeted radioimmunotherapy (PRIT) based on the inverse electron demand Diels–Alder (IEDDA) reaction between tetrazine (Tz) and <i>trans</i>-cyclooctene (TCO) represents a promising strategy for leveraging the affinity and specificity of antibodies without their pharmacokinetic drawbacks. Herein, we present an investigation of the <i>in vivo</i> efficacy and dosimetry of a PRIT strategy for colorectal carcinoma based on the ligation between a ¹⁷⁷Lu-labeled Tz radioligand (¹⁷⁷Lu-DOTA-PEG₇-Tz) and a TCO-bearing immunoconjugate of the huA33 antibody (huA33-TCO). Biodistribution studies in tumor-bearing mice using intervals of 24, 48, and 72 h between the administration of huA33-TCO and ¹⁷⁷Lu-DOTA-PEG₇-Tz revealed that a 24 h lag time produced the most promising <i>in vivo</i> results: high activity concentrations in the tumor (21.2 %ID/g ± 2.9 at 24 h postinjection), low uptake in nontarget tissues, and favorable dosimetry (an effective dose of 0.054 mSv/MBq). A subsequent longitudinal therapy study revealed striking differences between both the survival and tumor growth of the treatment and control cohorts, clearly underscoring the promise of this approach for the radiotherapy of colorectal carcinoma

State of Cancer Care in America: Achieving Cancer Health Equity Among Sexual and Gender Minority Communities

In 2017, ASCO issued the position statement, Strategies for Reducing Cancer Health Disparities Among Sexual and Gender Minority Populations, outlining five areas of recommendations to address the needs of both sexual and gender minority (SGM, eg, LGBTQ+) populations affected by cancer and members of the oncology workforce who identify as SGM: (1) patient education and support; (2) workforce development and diversity; (3) quality improvement strategies; (4) policy solutions; and (5) research strategies. In 2019, ASCO convened the SGM Task Force to help actualize the recommendations of the 2017 position statement. The percentage of the US population who publicly identify as SGM has increased dramatically over the past few years. Although increased national interest in SGM health equity has accompanied a general interest in research, policy change, and education around diversity, equity, and inclusion, resulting from public concern over discrimination in health care against Black, Indigenous, and People of Color, this has been accompanied by a surge in discriminatory legislation directly impacting the SGM community. Although much progress has been made in advancing SGM cancer health equity since 2017, more progress is needed to reduce disparities and advance equity. The five focus areas outlined in the 2017 ASCO position statement remain relevant, as we must continue to promote and advance equity in quality improvement, workforce development, patient care, research, and SGM-affirming policies. This article reports on the progress toward reducing SGM cancer disparities and achieving equity across these five areas and identifies future directions for the work that still remains

First row metal complexes of the hindered tridentate ligand 2,6-bis-(3′,5′-diphenylpyrazolyl)pyridine

Crystal structures of five first-row transition metal complexes of a recently-available bis-pyrazolylpyridine (bpp) ligand, 2,6-bis(3′,5′-diphenylpyrazolyl)pyridine (bdppp), prepared by reaction with transition metal chlorides, are reported. The ligand forms two types of structures, a 2:1 complex with Fe (II) chloride, and 1:1 complexes with Mn(II), Ni(II), Co(II), and Zn(II), chlorides, resulting in two different geometries. In all cases the ligand is tridentate, but in contrast to reported bpp structures, the plane of the pyridine ring coordinating with the metal is significantly distorted from the plane of the pyrazoles and metal

Long-term outcomes among 2-year survivors of autologous hematopoietic cell transplantation for Hodgkin and diffuse large b-cell lymphoma

Autologous hematopoietic cell transplantation (auto-HCT) is a standard therapy for relapsed classic Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL); however, long-term outcomes are not well described. This study analyzed survival, nonrelapse mortality, late effects, and subsequent malignant neoplasms (SMNs) in 1617 patients who survived progression-free for ≥2 years after auto-HCT for cHL or DLBCL between 1990 and 2008. The median age at auto-HCT was 40 years; the median follow-up was 10.6 years. The 5-year overall survival rate was 90% (95% confidence interval [CI], 87%-92%) for patients with cHL and 89% (95% CI, 87%-91%) for patients with DLBCL. The risk of late mortality in comparison with the general population was 9.6-fold higher for patients with cHL (standardized mortality ratio [SMR], 9.6) and 3.4-fold higher for patients with DLBCL (SMR, 3.4). Relapse accounted for 44% of late deaths. At least 1 late effect was reported for 9% of the patients. A total of 105 SMNs were confirmed: 44 in the cHL group and 61 in the DLBCL group. According to a multivariate analysis, older age, male sex, a Karnofsky score < 90, total body irradiation (TBI) exposure, and a higher number of lines of chemotherapy before auto-HCT were risk factors for overall mortality in cHL. Risk factors in DLBCL were older age and TBI exposure. A subanalysis of 798 adolescent and young adult patients mirrored the outcomes of the overall study population. Despite generally favorable outcomes, 2-year survivors of auto-HCT for cHL or DLBCL have an excess late-mortality risk in comparison with the general population and experience an assortment of late complications. Cancer 2018;124:816-25. © 2017 American Cancer Society