Background
Radiolabeled-antibodies usually display non-specific liver accumulation that may impair image analysis and antibody biodistribution. Here, we investigated whether Fc silencing influenced ...antibody biodistribution. We compared recombinant
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Zr-labeled antibodies (human IgG1 against different targets) with wild-type Fc and with mutated Fc (LALAPG triple mutation to prevent binding to Fc gamma receptors; FcγR). After antibody injection in mice harboring xenografts of different tumor cell lines or of immortalized human myoblasts, we analyzed antibody biodistribution by PET-CT and conventional biodistribution analysis.
Results
Accumulation in liver was strongly reduced and tumor-specific targeting was increased for the antibodies with mutated Fc compared with wild-type Fc.
Conclusion
Antibodies with reduced binding to FcγR display lower liver accumulation and better tumor-to-liver ratios. These findings need to be taken into account to improve antibody-based theragnostic approaches.
Palbociclib is a good candidate for therapeutic drug monitoring (TDM) due to its narrow therapeutic range and frequency of toxicities, particularly high-grade neutropenia. In this prospective, ...bicentric clinical trial, we evaluated the palbociclib exposure−toxicity relationship and determined the relevant sources of palbociclib pharmacokinetic variability, including drug−drug interactions (DDI). We followed 58 patients (mean age: 62.9 years) for 1 year. The geometric median of palbociclib plasma trough concentration (Ctrough) was 74.1 ng/mL. Neutropenia occurred in 70.7% of patients (high grade in 67.2% of patients). High-grade neutropenia occurrence during the first two palbociclib cycles was higher in patients with lower neutrophil count at initiation (p = 0.002). Palbociclib plasma Ctrough was correlated with high-grade neutropenia occurrence during the first two cycles (p = 0.024, OR 5.51). Co-treatment with agents that may interfere with palbociclib PK significantly influenced palbociclib Ctrough (p < 0.05). CYP3A4/P-glycoprotein inhibitors increased by 25% palbociclib Ctrough (p = 0.035), while antacids reduced it by 20% (p = 0.036). However, DDI did not have any significant effect on high-grade neutropenia occurrence (p > 0.05). This study confirms the major role of TDM to manage palbociclib safe use from the first week of treatment, particularly the significant incidence of hematological toxicity. Moreover, this first dedicated prospective study confirmed the importance of characterizing co-treatments to limit the DDI risk with oral-targeted therapies.
Antibody-based therapeutics have become a major class of therapeutics with over 120 recombinant antibodies approved or under review in the EU or US. This therapeutic class has experienced a ...remarkable expansion with an expected acceleration in 2021–2022 due to the extraordinary global response to SARS-CoV2 pandemic and the public disclosure of over a hundred anti-SARS-CoV2 antibodies. Mainly delivered intravenously, alternative delivery routes have emerged to improve antibody therapeutic index and patient comfort. A major hurdle for antibody delivery and efficacy as well as the development of alternative administration routes, is to understand the different natural and pathological barriers that antibodies face as soon as they enter the body up to the moment they bind to their target antigen. In this review, we discuss the well-known and more under-investigated extracellular and cellular barriers faced by antibodies. We also discuss some of the strategies developed in the recent years to overcome these barriers and increase antibody delivery to its site of action. A better understanding of the biological barriers that antibodies have to face will allow the optimization of antibody delivery near its target. This opens the way to the development of improved therapy with less systemic side effects and increased patients’ adherence to the treatment.
Monoclonal antibody (mAb)-based immunotherapy is booming in oncology. In 2020, more than 40% of FDA (Food and Drug Administration)-approved antibodies (34 out of 84 antibodies, according to The ...Antibody Society) have an indication for cancer therapy. In contrast to standard chemotherapy, they demonstrate a much better safety profile for patients. Despite this, adverse side effects may occur due to the targeting of the antigen also expressed by healthy tissues. For this reason, emerging strategies aim at optimizing the antibody format and considering the particularities of the tumor microenvironment to confer a more specific action of the antibody at the tumor site.
L’immunothérapie à base d’anticorps monoclonaux (AcM) connaît un plein essor en cancérologie. En 2020, plus de 40% des anticorps approuvés par la FDA (
Food and Drug Administration
) (34 sur 84 ...anticorps, selon
The Antibody Society
) ont une indication pour les thérapies anti-cancéreuses. Contrairement à la chimiothérapie standard, ils démontrent un bien meilleur profil de tolérance pour les patients. Malgré cela, des effets indésirables néfastes peuvent survenir en raison du ciblage de l’antigène qui est également exprimé au niveau des tissus sains. C’est pourquoi des stratégies émergentes visent à optimiser le format des anticorps et à tenir compte des particularités du microenvironnement tumoral pour conférer une action encore plus spécifique de l’anticorps au niveau tumoral.
Monoclonal antibody (mAb)-based immunotherapy is booming in oncology. In 2020, more than 40% of FDA (Food and Drug Administration)-approved antibodies (34 out of 84 antibodies, according to
The Antibody Society
) have an indication for cancer therapy. In contrast to standard chemotherapy, they demonstrate a much better safety profile for patients. Despite this, adverse side effects may occur due to the targeting of the antigen also expressed by healthy tissues. For this reason, emerging strategies aim at optimizing the antibody format and considering the particularities of the tumor microenvironment to confer a more specific action of the antibody at the tumor site.
•HPLC-MS/MS assay for palbociclib and ribociclib concomitant quantification in plasma.•Quantification of palbociclib exposure in patients with metastatic breast cancer.•Perspective therapeutic drug ...monitoring in patients treated with CDK4/6 inhibitors.•Impact of drug-drug interactions on palbociclib plasma concentration.
The CDK4/6 inhibitors palbociclib and ribociclib are kinase inhibitors used in association with hormonal therapy for the management of patients with metastatic breast cancer. Like most kinase inhibitors, therapeutic drug monitoring may be used for personalize their dosage. To this aim, we developed and validated a sensitive and specific HPLC-MS/MS method for palbociclib and ribociclib quantification in blood samples. We then quantified exposure to palbociclib (plasma trough concentration; Ctrough) in a real-life cohort of patients with locally invasive or metastatic breast cancer (n = 18) at day 15 of the first cycle of palbociclib treatment to characterize palbociclib concentration at steady state (Clinicaltrials.gov identifier NCT04025541, IdRCB n° 2018-A00064-51, 03/07/2018). The geometric mean (± standard deviation min-max) of palbociclib plasma Ctrough was 88.58 ng/mL (± 26.4 46.5 ng/mL – 133 ng/mL) at day 15. Some covariates, such as drug-drug interactions, could explain the concentration variations observed in our Caucasian cohort. These first results in real-life settings obtained with our HPLC-MS/MS method give important information on palbociclib monitoring and pharmacokinetic variability.
To compare the outcomes of ultrasound guided foam sclerotherapy (UGFS) and endovenous laser ablation (EVLA) to treat isolated small saphenous vein (SSV) incompetence in a multicentre randomised ...controlled study (RCT; ClinicalTrials.gov identifier: NCT05468450).
Patients aged ≥ 18 years undergoing isolated SSV treatment (reflux > 0.5 seconds) were randomised to UGFS or EVLA. Patients treated with UGFS were allowed one additional truncal treatment at six weeks. Tributary treatments (phlebectomy or sclerotherapy) were permitted after six months. Participants were assessed at eight days, six months, and one, two, and three years. The primary endpoint was the absence of SSV reflux (> 0.5 seconds). Secondary outcomes included clinical scores and quality of life (QoL) scores. All analyses were done by intention to treat.
Of 1 522 screened patients, 161 were randomised to UGFS (n = 82) and EVLA (n = 79). Only 3% of patients who received UGFS had the second (allowed) treatment and 86% of patients completed the three year study. Forty-one and 19 tributary treatments (by sclerotherapy) were performed in 27 UGFS patients (33%) and 15 EVLA patients (19%), respectively. The complete absence of reflux at three years was significantly better after EVLA (86%) than after UGFS (56%) (odds ratio OR 5.36, 95% confidence interval CI 2.31 – 12.44; risk ratio 1.59, 95% CI 1.26 – 2.01). Two deep vein thromboses (DVTs; one femoropopliteal and one gastrocnemius) and one endovenous heat induced thrombosis occurred in the EVLA group. Seven DVTs were seen in the UGFS group, including two partial popliteal DVTs and five gastrocnemius vein thromboses (four asymptomatic and incidental on day 8 screening). At three years, there was no difference between groups for the following: rate of visible varices (p = .87), revised Venous Clinical Severity Score (p = .28), and QoL (p = .59). Patient satisfaction scores were high in both groups (median score: EVLA 97/100 and UGFS 93/100; p = .080). Symptoms were significantly improved in both groups. (p < .001)
Technical success was better for EVLA than for UGFS three years after SSV treatment. This agrees with studies that have reported on these treatments in the great saphenous vein. However, improvements in clinical outcome were similar for both groups.
The aim was to evaluate the distribution of the diameter of the great saphenous vein (GSV) at mid-thigh level and to investigate its association with clinical class, symptoms, and proximal extent of ...reflux.
Vascular physicians, members of the French Society of Phlebology, were invited to participate in a consecutive observational study in patients presenting with symptoms and/or signs of uni- or bilateral chronic venous disorders (CVDs) in previously untreated limbs (clinical class of the CEAP classification C0s – C6). Patients were included between January and March 2015. They completed a specially designed venous symptoms questionnaire. Duplex ultrasound of the included limbs was performed with the patient standing to detect reflux in the GSV and to measure the GSV inner diameter at mid-thigh.
Between January and March 2015, 35 physicians examined 1245 patients (2450 limbs after excluding 40 limbs): 77% were female, mean age 52 ± 14; 69% of the patients had venous symptoms in one or both legs. The most frequent symptoms were feeling of heaviness, feeling of swelling and aching. Predominant CEAP clinical classes were C2 (38% of limbs) and C1 (35%). In case of GSV reflux (40% of limbs), the average diameter was 5.6 ± 2 mm and the distribution was 62% < 6 mm, 30% between 6 and 8 mm, and 8% > 8 mm. The study showed a clear association between clinical class and GSV diameter (the higher the clinical class, the larger the diameter; p < .0001), between venous symptoms and diameter (the larger the diameter, the higher the intensity of symptoms, p < .0001 for overall discomfort) and between proximal extent of reflux and diameter (the more proximal the extent of reflux, the larger the diameter, p < .0001).
The DIAGRAVES study demonstrated that in France for patients consulting with CVDs, more than half of the incompetent GSVs had a diameter < 6 mm, while large diameters were relatively infrequent. This should be kept in mind when considering management strategies in patients with CVDs.
Although officially created, the protected reserve of Ngiri remains virtual, existing only on paper, many reasons can explain this hypothesis: - The insufficient national regulations, at least at the ...time of the establishment of this protected reserve, which had the effect of not having any application at the local level. - Conflicts of administrative and community interest arising from the overlapping of different laws or measures. - The authorities' lack of interest in safeguarding biodiversity or the priorities given to other aspects of environmental management (development of fishing). - The local situation too complicated due to various conflicts between fishermen and eco-guards. - The lack of qualified personnel, of means, in particular financial resources, to implement measures for the sustainable management of the reserve. - The lack of skills in assessing the state of the environment and planning management. - The poor definition of the limits of the protected reserve, thus reducing its interest for the fauna and flora. - The very significant human pressure on the outskirts and the lack of ecological corridors to connect the reserve. - The lack of economic valuation of the said reserve.
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