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Review of dose justifications for antibody-drug conjugate approvals from clinical pharmacology perspective: A focus on exposure-response analyses.
No full textAntibody-drug conjugates (ADCs) are revolutionizing cancer treatment by specific targeting of the cancer cells thereby improving the therapeutic window of the drugs. Nevertheless, they are not free from unwanted toxicities mainly resulting from non-specific targeting and release of the payload. Therefore, the dosing regimen must be optimized through integrated analysis of the risk-benefit profile, to maximize the therapeutic potential. Exposure-response (E-R) analysis is one of the most widely used tools for risk-benefit assessment and it plays a pivotal role in dose optimization of ADCs. However, compared to conventional E-R analysis, ADCs pose unique challenges since they feature properties of both small molecules and antibodies. In this article, we review the E-R analyses that have formed the key basis of dose justification for each of the 12 ADCs approved in the USA. We discuss the multiple analytes and exposure metrics that can be utilized for such analysis and their relevance for safety and efficacy of the treatment. For the endpoints used for the E-R analysis, we were able to uncover commonalities across different ADCs for both safety and efficacy. Additionally, we discuss dose optimization strategies for ADCs which are now a critical component in clinical development of oncology drugs
Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence.
No full textGlioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment response was mediated by perivascular-derived fibroblast-like cells via activation by transforming growth factor β (TGF-β) signaling and neuroinflammation. Concordantly, combinatorial inhibition of these pathways inhibited treatment-associated fibrosis, and significantly improved survival in preclinical trials of anti-colony-stimulating factor-1 receptor (CSF-1R) therapy
Scalability of Pharmaceutical Formation by Mechanochemistry in batch.
No full textThe development of mechanochemistry is considerably growing. Benign by design, this technology complies with several principles of green chemistry, contributing to the achievement of the United Nations Sustainable Development Goals (UN SDGs) and the European Green Deal objectives. Herein, we report the use of mechanochemical processes in batch to prepare kilogram-scale of the Active Pharmaceutical Ingredient (API): Ibuprofen-Nicotinamide (IBP-NCT) co-crystal in an industrial eccentric vibration mill. This scenario shows a sustainable approach to the industrial up-scaling of pharmaceutical co-crystals by a solvent-free mechanochemical process in batch. The quantitatively assessment of the greenness of the mechanochemical process against the Twelve Principles of Green Chemistry was performed using the DOZN 2.0 Green Chemistry Evaluator
Dose Justification for Asciminib in Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia With and Without the T315I Mutation
No full textPurpose: Asciminib is approved in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥2 prior tyrosine kinase inhibitors. Here, we demonstrate the similarity in efficacy/safety of asciminib 80 mg once daily (q.d.) versus 40 mg twice daily (b.i.d.) in patients with CML-CP without T315I mutation and support the use of the 200 mg b.i.d. dosage in patients harboring T315I mutation.
Patients and Methods: Data were collected from 199 patients in the Phase 1 (NCT02081378; 10−200 mg b.i.d. or 10−400 mg q.d.) and 154 patients in the Phase 3 (NCT03106779; 40 mg b.i.d.) studies. Evaluations were based on population pharmacokinetics (PopPK) and exposure-response (efficacy/safety) analyses.
Results: The PopPK analysis showed comparable exposure (area under the curve, AUC0-24h) for 40 mg b.i.d. and 80 mg q.d. (12,638 vs 12,646 ng*h/mL); average maximum and minimum plasma concentrations for 80 mg q.d. were 1.61- and 0.72-fold those of 40 mg b.i.d., respectively. Exposure-response analyses revealed similar predicted major molecular response rates for 40 mg b.i.d. and 80 mg q.d. (Week 24: 27.6% vs 24.8%; Week 48: 32.3% vs 30.6%). Results also established adequacy of 200 mg b.i.d. in patients with T315I mutation (Week 24: 20.7%; Week 48: 23.7%), along with a similar safety profile for all dose regimens.
Conclusions: A daily dose of 80 mg asciminib (40 mg b.i.d. or 80 mg q.d.) demonstrated substantial efficacy with well-tolerated safety in patients with CML-CP without T315I mutation, while 200 mg b.i.d. asciminib was appropriate for patients with T315I mutation
Nonclinical and clinical characterization of MAU868, a novel human-derived monoclonal neutralizing antibody targeting BK polyomavirus VP1.
No full textReactivation of BK polyomavirus (BKPyV) can cause significant kidney and bladder disease in immunocompromised patients. There are currently no effective, BKPyV-specific therapies. MAU868 is a novel, human immunoglobulin (Ig) G1 monoclonal antibody that binds the major capsid protein, VP1, of BKPyV with picomolar affinity, neutralizes infection by the 4 major BKPyV genotypes (EC50 ranging from 0.009-0.093 μg/mL; EC90 ranging from 0.102-4.160 μg/mL), and has comparable activity against variants with highly prevalent VP1 polymorphisms. No resistance-associated variants were identified in long-term selection studies, indicating a high in vitro barrier-to-resistance. The high-resolution crystal structure of MAU868 in complex with VP1 pentamer identified 3 key contact residues in VP1 (Y169, R170, and K172). A first-in-human study was conducted to assess the safety, tolerability, and pharmacokinetics of MAU868 following intravenous and subcutaneous administration to healthy adults in a randomized, placebo-controlled, double-blinded, single ascending dose design. MAU868 was safe and well-tolerated. All adverse events were grade 1 and resolved. The pharmacokinetics of MAU868 was typical of a human IgG, with dose-proportional systemic exposure and an elimination half-life ranging between 23 and 30 days. These results demonstrate the potential of MAU868 as a first-in-class therapeutic agent for the treatment or prevention of BKPyV disease
Label-free assessment of complement-dependent cytotoxicity of therapeutic antibodies via a whole-cell MALDI mass spectrometry bioassay.
No full textPotency assessment of monoclonal antibodies or corresponding biosimilars in cell-based assays is an essential prerequisite in biopharmaceutical research and development. However, cellular bioassays are still subject to limitations in sample throughput, speed, and often need costly reagents or labels as they are based on an indirect readout by luminescence or fluorescence. In contrast, whole-cell Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) Mass Spectrometry (MS) has emerged as a direct, fast and label-free technology for functional drug screening being able to unravel the molecular complexity of cellular response to pharmaceutical reagents. However, this approach has not yet been used for cellular testing of biologicals. In this study, we have conceived, developed and benchmarked a label-free MALDI-MS based cell bioassay workflow for the functional assessment of complement-dependent cytotoxicity (CDC) of Rituximab antibody. By computational evaluation of response profiles followed by subsequent m/z feature annotation via fragmentation analysis and trapped ion mobility MS, we identified adenosine triphosphate and glutathione as readily MS-assessable metabolite markers for CDC and demonstrate that robust concentration-response characteristics can be obtained by MALDI-TOF MS. Statistical assay performance indicators suggest that whole-cell MALDI-TOF MS could complement the toolbox for functional cellular testing of biopharmaceuticals
Preface for Special Issue: “Emerging strategies, technologies and approaches for the next generation ADCs”
No full text1. Antibody-drug conjugates (ADCs) represent an advanced category of biotherapeutic agents, typically consisting of an antibody irreversibly bound to a biologically-active cytotoxic agent. Since the first ADC, MylotargTM, was approved in 2000, there have been fifteen ADCs sanctioned to date, with thirteen receiving approval from the FDA for the treatment of a variety of cancers, including blood malignancies and solid tumors.
2. In this Special Issue of Xenobiotica focusing on ADCs, our goal is to compile a collection of papers, featuring both original research and review articles authored by specialists in academia and the pharmaceutical industry, to showcase some of the historical insights gained, current progress, and future prospects to enhance comprehension and tackle obstacles in the field of ADC development for cancer therapy.
3. This special issue features articles that evaluate key components of ADC development, including payload design, innovative linker chemistries, and the use of new technologies for site-specific conjugations beyond traditional engineered cysteines. It also spotlights cutting-edge ADC structures like bispecific ADCs, dual-payload ADCs, targeted nanoparticles and antibody oligonucleotide conjugates (AOCs).
4. Several other papers discuss bioanalytical and ADME strategies for ADCs as well. In addition, approaches to improve the translation of pharmacokinetics, safety, and therapeutic index (TI) of ADCs are presented
Climbing the longevity pyramid: overview of evidence-driven healthcare prevention strategies for human longevity
No full textLongevity medicine is an emerging and iterative healthcare discipline focusing on early detection, preventive measures, and personalized approaches that aim to extend healthy lifespan and promote healthy aging. This comprehensive review introduces the innovative concept of the “Longevity Pyramid.” This conceptual framework delineates progressive intervention levels, providing a structured approach to understanding the diverse strategies available in longevity medicine. At the base of the Longevity Pyramid lies the level of prevention, emphasizing early detection strategies and advanced diagnostics or timely identification of potential health issues. Moving upwards, the next step involves lifestyle modifications, health-promoting behaviors, and proactive measures to delay the onset of age-related conditions. The Longevity Pyramid further explores the vast range of personalized interventions, highlighting the importance of tailoring medical approaches based on genetic predispositions, lifestyle factors, and unique health profiles, thereby optimizing interventions for maximal efficacy. These interventions aim to extend lifespan and reduce the impact and severity of age-related conditions, ensuring that additional years are characterized by vitality and wellbeing. By outlining these progressive levels of intervention, this review offers valuable insights into the evolving field of longevity medicine. This structured framework guides researchers and practitioners toward a nuanced strategic approach to advancing the science and practice of healthy aging
Peak Purity Assessments in Forced Degradation Studies - an Industry Perspective
No full textThis review article discusses scientific rationales and current best practices in pharmaceutical industry for performing chromatographic peak purity assessment (PPA) activities associated with the stability indicating analytical methods applicable to a regulatory submission. The discussion includes a comprehensive overview of PPA related regulatory landscape and common approaches to obtain PPA results, as well as strength and weakness of UV and mass spectrometry facilitated spectral PPA. The article also summarizes industry’s current best practice to assess and mitigate the risk of impure peak and is concluded with science-based recommendations to guide peak purity assessment
Correlative light-electron microscopy methods to characterize the ultrastructural features of the replicative and dormant liver stages of malaria
No full textBackground:
The infection of the liver is an obligatory step leading to malaria disease. Following hepatocyte invasion, malaria parasites either differentiate into liver stage schizonts or hypnozoites, which can lie dormant for extended periods of time before reactivating and causing relapses. The liver stages of malaria remain elusive because of technical challenges hindering access to well-established technologies, including electron microscopy. A deeper understanding of hypnozoite biology could prove essential in the development of radical cure therapeutics against malaria.
Results:
The liver stages of the non-relapsing rodent parasite Plasmodium berghei and the relapsing simian parasite Plasmodium cynomolgi were characterized in human Huh7 cells or primary monkey hepatocytes using Correlative Light-Electron Microscopy (CLEM). Specifically, CLEM approaches that rely on GFP-expressing P. berghei (GFP-CLEM) or on immunofluorescence assays (IFA-CLEM) for both P. berghei and P. cynomolgi were used for imaging of liver stages. The results from P. berghei showed that host and parasite organelles can be identified and imaged at high resolution using both CLEM approaches. However, while IFA-CLEM was associated with more pronounced extraction of cellular content, samples’ features were generally well preserved. Using IFA-CLEM, a collection of micrographs was acquired for P. cynomolgi liver stage schizonts and hypnozoites, demonstrating the potential of this approach as a useful tool for characterizing the liver stages of relapsing malaria species.
Conclusions:
We developed a CLEM protocol for imaging the liver stages of malaria species that are difficult to study due to a lack of established genetic systems. This study also provides a dataset that characterizes the ultrastructural features of liver stage schizonts and hypnozoites from the relapsing simian malaria species P. cynomolgi