Antibody-drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic ...payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.
The epidermal growth factor receptor (EGFR) is overexpressed in a variety of human epithelial tumors, often as a consequence of gene amplification. Tumors with EGFR gene amplification frequently ...contain EGFR gene rearrangements, with the most common extracellular domain mutation being EGFRvIII. This mutation leads to a deletion of exons 2–7 of the EGFR gene and renders the mutant receptor incapable of binding any known ligand. Despite this, EGFRvIII displays low‐level constitutive signaling that is augmented by reduced internalization and downregulation. Aberrant EGFRvIII signaling has been shown to be important in driving tumor progression and often correlates with poor prognosis. It is clear that EGFRvIII is expressed in a considerable proportion of patients with glioblastoma multiforme (GBM). The presence of EGFRvIII in other tumor types, however, remains controversial. In this review, we critically analyze the evidence for the expression of EGFRvIII in a range of tumor types and discuss recent findings pertinent to its function and biology in GBM.
Tumors with EGFR gene amplification frequently contain EGFR gene rearrangements, with the most common extracellular domain mutation being EGFRvIII. This EGFR deletion mutation is incapable of binding ligand, yet EGFRvIII displays low‐level constitutive signaling augmented by reduced internalization. We analyze the evidence for EGFRvIII expression in different tumor types and discuss recent findings regarding its tumorigenic properties in brain cancer.
The advent of immune checkpoint‐inhibitors (CPI) has transformed treatment for several cancer types. This review was performed to assess the rate of adverse events (AEs) associated with the use of ...CPI, alone or in combinations. A review of AEs reporting quality was also performed. All publications of Randomized Clinical Trials (RCTs) assessing CPI published before December 2017 were included. To investigate the quality of AEs reporting, a set of items was defined based on the 2004 CONSORT harms extension statement. Rates of Grade 5, serious, and study‐withdrawal related AEs were collected in each treatment category. Specific immune related AEs (irAEs) were also collected when available. Pooled estimates of adverse event rates were calculated by using generalized linear mixed model. A total of 35 RCTs including 16,485 patients were included. The overall quality of AEs reporting was satisfactory, but items pertaining to methods of data collection and analysis were infrequently reported. Grade ≥ 3 AEs were reported for 14% (95% CI 12–16) of patients treated with PD(L)‐1 inhibitors, 34% (95% CI 27–42) of patients treated with CTLA‐4 inhibitors, 55% (95% CI 51–59) of patients on CPI combinations and 46% (95% CI 40–53) of patients on immunotherapy‐chemotherapy combination. The profile of irAEs was different among the treatment categories. The use of CPI, especially in combination, is associated with significant rates of Grade ≥ 3 AEs. Healthcare planning should anticipate the expected high number of patients presenting with irAEs in the future.
What's new?
Even the most promising therapies are of little value in the clinic if they're too toxic. With the advent of new immunotherapies, evaluating benefit vs. risk has become more complex than for standard chemotherapies. In this analysis, the authors found that treatment with immune checkpoint‐inhibitors (CPI) is associated with significant rates of adverse events (AEs) of Grade≥3, especially when used in combination with other types of therapy. Healthcare planning should anticipate an increased number of patients presenting with immune‐related and other AEs in the future.
•Monoclonal antibodies are effective treatment for various cancers and autoimmune diseases.•Immune checkpoint therapy in cancer has emerged as a potent therapeutic approach.•Autoimmune disease ...control with monoclonal antibodies is highly successful.•Resistance mechanisms have emerged as a major issue in therapeutic efficacy.
Since Nobel laureate Paul Ehrlich proposed the concept of magic bullet in 1906, Köhler and Milstein discovered Hybridoma technology in 1975, and Greg Winter pioneered the technique to humanize monoclonal antibodies in 1988, monoclonal antibodies have been successfully developed to treat medical illnesses. Monoclonal antibodies are effective treatments for inhibition of alloimmune reactivity, haematological malignancies, solid organ malignancies, viral illnesses and are also used as antiplatelet therapy. Their successful use in cancer and autoimmune diseases in humans have made them one of the fastest growing classes of new drugs approved for these indications in last few decades. This review focuses on the role of monoclonal antibodies as an immunomodulatory therapy against cancer and autoimmune diseases, the strategies used to enhance efficacy, and how resistance mechanisms are being addressed to improve therapeutic outcomes for patients.
The pandemic of coronavirus disease 2019 (COVID‐19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has caused an unprecedented global social and economic impact, and ...high numbers of deaths. Many risk factors have been identified in the progression of COVID‐19 into a severe and critical stage, including old age, male gender, underlying comorbidities such as hypertension, diabetes, obesity, chronic lung diseases, heart, liver and kidney diseases, tumors, clinically apparent immunodeficiencies, local immunodeficiencies, such as early type I interferon secretion capacity, and pregnancy. Possible complications include acute kidney injury, coagulation disorders, thoromboembolism. The development of lymphopenia and eosinopenia are laboratory indicators of COVID‐19. Laboratory parameters to monitor disease progression include lactate dehydrogenase, procalcitonin, high‐sensitivity C‐reactive protein, proinflammatory cytokines such as interleukin (IL)‐6, IL‐1β, Krebs von den Lungen‐6 (KL‐6), and ferritin. The development of a cytokine storm and extensive chest computed tomography imaging patterns are indicators of a severe disease. In addition, socioeconomic status, diet, lifestyle, geographical differences, ethnicity, exposed viral load, day of initiation of treatment, and quality of health care have been reported to influence individual outcomes. In this review, we highlight the scientific evidence on the risk factors of severity of COVID‐19.
Summary
Elucidating the temporal dynamics of arbuscular mycorrhizal (AM) fungi is critical for understanding their functions. Furthermore, research investigating the temporal dynamics of AM fungi in ...response to agricultural practices remains in its infancy.
We investigated the effect of nitrogen fertilisation and watering reduction on the temporal dynamics of AM fungi, across the lifespan of wheat.
Nitrogen fertilisation decreased AM fungal spore density (SD), extraradical hyphal density (ERHD), and intraradical colonisation rate (IRCR) in both watering conditions. Nitrogen fertilisation affected AM fungal community composition in soil but not in roots, regardless of watering conditions. The temporal analysis revealed that AM fungal ERHD and IRCR were higher under conventional watering and lower under reduced watering in March than in other growth stages at low (≤ 70 kg N ha−1 yr−1) but not at high (≥ 140) nitrogen fertilisation levels. AM fungal SD was lower in June than in other growth stages and community composition varied with plant development at all nitrogen fertilisation levels, regardless of watering conditions.
This study demonstrates that high nitrogen fertilisation levels disrupt the temporal dynamics of AM fungal hyphal growth but not sporulation and community composition.
As a kind of lightweight structure with great economic benefits, metal/composite hybrid structure is raising rapidly among automobile safety components due to its excellent anti‐collision ...performance. In this paper, a new design was developed by introducing an induced circular hole to improve the energy absorption performance of the AL/CFRP hybrid thin‐walled tubes under different loading conditions. Quasi‐static experiments and finite element simulation were carried out on the hybrid tubular sample with induced circular holes, and the crash resistance of the number and diameter of induced round holes under different loading angles (θ) of 0°,10°, 20°, and 30° was analyzed through the verified finite element model. The results showed that the induction hole can effectively reduce the peak load and improve the energy absorption characteristics of the hybrid thin‐walled tube under the axial (0°) load. Under the inclined load, the energy absorption capacity of all samples decreased to different degrees with increasing loading angle, and the induced hole changed the deformation mode of the hybrid tube, especially under the 30° loading angle. The complex proportional assessment is then implemented on the optimal structures, and specific energy absorption, peak crush force, and crush force efficiency were selected as the objective functions to improve the overall impact resistance under different loading angles. Considering three design cases, the AL/CFRP hybrid thin‐walled structure with three groups of induced holes are finally found as the best energy absorbing devices. The work in this paper can provide a guide for the design of advanced energy absorbing devices for arbitrary loading condition.
Within a microscopic transport model, systematic investigation of hyperon production and hypernucleus formation up to strangeness S=−2 is carried out for 197Au + 197Au and 40Ca + 40Ca at the incident ...energy of 3A GeV. The spatial, temporal and density distributions of hyperon production, absorption and chemical freeze-out are investigated from novel perspectives. The rapidity and kinetic energy spectra of Ξ hyperons and double Λ hypernuclei are analyzed. It is revealed that the chemical balance of hyperon production is established in baryon-baryon channels while the opposite result is found in baryon-meson channels. It turns out that the rapidity spectra of ΛΛ4,5X are single-peak and more than two orders of magnitude lower than that of Λ3H. Formation of double Λ hypernuclei through Ξ hypernuclei as intermediate states is also discussed in terms of kinematics. Production of light double Λ hypernuclei, i.e., ΛΛ4,5H, ΛΛ4−7He, ΛΛ5Li is estimated to be at a level of μb in the case of 197Au + 197Au and two further orders of magnitude lower in that of 40Ca + 40Ca collisions.
Objectives: With aging, older adults are at risk of a decline in mental health as they experience significant life stressors that are specific to later life. It is thus important to explore the ...potential of suitable approaches that promote healthy aging, to address the mental health needs of older adults. Pet ownership has been found to be associated with positive mental health outcomes; however, there is limited research on the lived experience and meaning derived from pet ownership. The purpose of this study was to explore pet ownership in community-dwelling older adults and its influence on mental health.
Methods: Semi-structured interviews were conducted with 14 community-dwelling older adults who were aged 65 and above and pet owners. Participants were interviewed individually on a single occasion about the meaning derived from the role of pet ownership and howthey perceived that their pet influenced their mental health.
Results: Results were analysed using Colaizzi's phenomenological framework and four themes emerged from the interviews: pets provide (i) comfort and safety; (ii) social inclusion and participation; (iii) purposeful routine and structure; and (iv) a meaningful role.
Conclusion: These findings suggest that the role of pet ownership may benefit community-dwelling older adults by providing companionship, giving a sense of purpose and meaning, reducing loneliness and increasing socialisation. These benefits may also increase resilience in older adults against mental health disorders, which may positively influence their mental health outcomes.
Radioimmunoconjugates consist of a monoclonal antibody (mAb) linked to a radionuclide. Radioimmunoconjugates as theranostics tools have been in development with success, particularly in hematological ...malignancies, leading to approval by the US Food and Drug Administration (FDA) for the treatment of non-Hodgkin's lymphoma. Radioimmunotherapy (RIT) allows for reduced toxicity compared to conventional radiation therapy and enhances the efficacy of mAbs. In addition, using radiolabeled mAbs with imaging methods provides critical information on the pharmacokinetics and pharmacodynamics of therapeutic agents with direct relevance to the optimization of the dose and dosing schedule, real-time antigen quantitation, antigen heterogeneity, and dynamic antigen changes. All of these parameters are critical in predicting treatment responses and identifying patients who are most likely to benefit from treatment. Historically, RITs have been less effective in solid tumors; however, several strategies are being investigated to improve their therapeutic index, including targeting patients with minimal disease burden; using pre-targeting strategies, newer radionuclides, and improved labeling techniques; and using combined modalities and locoregional application. This review provides an overview of the radiolabeled intact antibodies currently in clinical use and those in development.
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