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Therapeutic proteins (TPs) are becoming increasingly important as therapeutic agents. A consequence of expanding their clinical indications is coadministration with well-established small-molecule drugs (sMDs), which could lead to unpredictable effects. According to the existing regulatory guidance, the development of an sMD includes the evaluation...
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... Moreover, because data on neonatal stays were not available in our study, neonatal complications were studied only on the basis of maternal stays, which could lead to an underestimation of neonatal complications. Third, because of the very small number of women available for inclusion, we were not able to study the effect of the different anti-VEGF agents administered (bevacizumab, ranibizumab, or aflibercept) on obstetric complications, although they differ with regard to their pharmacokinetic and pharmacodynamic parameters [48]. Interestingly, bevacizumab and ranibizumab only bind to VEGF, whereas aflibercept also binds to the placental growth factor (PlGF). ...
This nationwide population-based cohort study aimed to describe the use of intravitreal injections (IVTs) of anti-vascular endothelial growth factor (anti-VEGF) agents and corticosteroids in pregnant women in France and to report on the incidence of obstetric and neonatal complications. All pregnant women in France who received any anti-VEGF or corticosteroid IVT during pregnancy or in the month preceding pregnancy from 1 January 2009 to 31 December 2018 were identified in the national medico-administrative databases. Between 2009 and 2018, there were 5,672,921 IVTs performed in France. Among these IVTs, 228 anti-VEGF or corticosteroid IVTs were administered to 139 women during their pregnancy or in the month preceding their pregnancy. Spontaneous abortion or the medical termination of pregnancy occurred in 10 women (16.1%) who received anti-VEGF agents and in one (3.1%) of the women who received corticosteroids (p = 0.09). This is the first national cohort study of pregnant women treated with anti-VEGF or corticosteroid IVTs. We found a high incidence of obstetric complications in pregnant women treated with anti-VEGF or corticosteroid IVTs but could not demonstrate a statistically significant association between the intravitreal agents and these complications. These agents should continue to be used with great caution in pregnant women.
... They display high affinity and tolerability, low drug−drug interactions, and low toxicity. 11 Other pharmacokinetic (PK) parameters of antibodies, such as high specificity and long half-life (t 1/2 ), are exploited by drug developers to deliver potent chemotherapeutic agents that by their toxicity or poor PK could not be otherwise administered to patients. Upon conjugation to antibodies/antibody fragments, they show decreasing off-target effects and/or improved PK. 12,13 Thus, the same strategy can be transposed to other diseases. ...
The frequency of brain disease has increased significantly in the past years. After diagnosis, therapeutic options are usually limited, which demands the development of innovative therapeutic strategies. The use of antibody−drug conjugates (ADCs) is promising but highly limited by the existence of the blood−brain barrier (BBB). To overcome the impermeability of this barrier, antibody fragments can be engineered and conjugated to BBB peptide shuttles (BBBpS), which are capable of brain penetration. Herein, we linked the highly efficient BBBpS, PepH3, to the IgG fragment crystallizable (Fc) domain using the streamlined expressed protein ligation (SEPL) method. With this strategy, we obtained an Fc-PepH3 scaffold that can carry different payloads. Fc-PepH3 was shown to be nontoxic, capable of crossing an in vitro cellular BBB model, and able to bind to the neonatal Fc receptor (FcRn), which is responsible for antibody long half-life (t 1/2). Overall, we demonstrated the potential of Fc-PepH3 as a versatile platform readily adaptable to diverse drugs of therapeutic value to treat different brain conditions.
... mAbs represent the fastest growing class of TPs. Currently, over 50 therapeutic antibodies are on the market [70]. They are complex molecules consisting of homodimers of variable and constant regions ( Figure 3) [71]. ...
... Thus, their exquisite specificity, high binding affinity, long half-life, low toxicity, and versatility are characteristics that contributed to antibodies' success [74,75]. Additionally, the low number of drug-drug interactions between mAbs and sMDs increased their combination in many therapeutic regimens [70]. ...
... The first mAb approved was muromonab-CD3 in the prevention of transplant rejection. Ever since, mAbs have been introduced in a number of therapeutic regimens in a wide range of conditions, such as organ transplantation (e.g., basiliximab and belatacept), inflammatory diseases (e.g., adalimumab and tocilizumab), and cancer (e.g., trastuzumab and cetuximab) [70]. The use of antibodies is increasing and improved mAb-based strategies will appear on the market in response to current therapeutic challenges (Figure 4). ...
The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood-brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells.
... Полагают, что базиликсимаб, связываясь с ИЛ-2-рецепторами на поверхности Т-лимфоцитов, вытесняет ИЛ-2 из комплекса с рецепторами. Высвободившийся ИЛ-2 начинает взаимодействовать со специфическими рецепторами в клетках печени и кишечника, влияя на активность CYP3A4 [42,43]. Сходный механизм может объяснять взаимодействие муромомаба и циклоспорина. ...
... We apologize for not explaining properly that mentioned drug interactions were related to the use of small molecules for pharmacological GO inhibition and not for siRNA approaches. We have modified the sentence in the revised version of the manuscript (L104-105) to clarify this point including a new reference that supports the concerns (Cavaco and Goncalves, 2017). ...
... The safety and efficacy of GO silencing in PH1 patients is currently being investigated in ongoing clinical trials (Alnylam Pharmaceuticals 2016, NCT02706886). However, although the use of small molecules or siRNAs can be effective to block disease-related pathways, they have limitations such as the requirement of multiple administrations for long-term effect 24 , incomplete inhibition of the target enzyme, compliance and potential interactions of the small molecules with other drugs/ treatments 27 . ...
CRISPR/Cas9 technology offers novel approaches for the development of new therapies for many unmet clinical needs, including a significant number of inherited monogenic diseases. However, in vivo correction of disease-causing genes is still inefficient, especially for those diseases without selective advantage for corrected cells. We reasoned that substrate reduction therapies (SRT) targeting non-essential enzymes could provide an attractive alternative. Here we evaluate the therapeutic efficacy of an in vivo CRISPR/Cas9-mediated SRT to treat primary hyperoxaluria type I (PH1), a rare inborn dysfunction in glyoxylate metabolism that results in excessive hepatic oxalate production causing end-stage renal disease. A single systemic administration of an AAV8-CRISPR/Cas9 vector targeting glycolate oxidase, prevents oxalate overproduction and kidney damage, with no signs of toxicity in Agxt1−/− mice. Our results reveal that CRISPR/Cas9-mediated SRT represents a promising therapeutic option for PH1 that can be potentially applied to other metabolic diseases caused by the accumulation of toxic metabolites.
This review evaluated the significance of therapeutic protein (TP)–drug interactions and the current practices for assessing the interaction potential. We reviewed US FDA labels of approved TPs with drug–drug interaction (DDI) assessment. TP–drug interactions have been evaluated from in vitro studies, animal studies, and/or clinical settings. Of the 150 FDA-approved TPs as of May 2019, 49 TP labels contained pharmacokinetic (PK)-related DDI information derived from at least one study method. Our review found that more than half of the clinical PK DDI evaluations showed no interaction, and no dose adjustment has been recommended for any of the rest TPs. The results and trends observed in this review may further enhance and inform risk-based approaches to evaluating the potential for TP–drug interactions.
Chimeric proteins composed of a biologically active peptide and a fragment crystallizable (Fc) domain of immunoglobulin G (IgG) are known as peptibodies. They present an extended half-life due to neonatal Fc receptor (FcRn) salvage pathway, a decreased renal clearance rate owing to its increased size (70 kDa) and, depending on the peptide used in the design of the peptibody, an active-targeting moiety. Also, the peptides therapeutic activity is boosted by the number of pep-tides in the fusion protein (at least two peptides) and to some peptides' alterations. Peptibodies are mainly obtained through recombinant DNA technology. However, to improve peptide properties , "unnatural" changes have been introduced to the original peptides' sequence, for instance, the incorporation of D-or non-natural amino acid residues or even cyclization thus, limiting the application of genetic engineering in the production of peptibodies, since these peptides must be obtained via chemical synthesis. This constrains prompted the development of new methods for conjugation of peptides to Fc domains. Another challenge, subject of intense research, relates to the large-scale production of such peptibodies using these new techniques, which can be minimized by their proved value. To date, two peptibodies, romiplostim and dulaglutide, have been approved and stay as the standard of care in their areas of action. Furthermore, a considerable number of peptibodies are currently in preclinical and clinical development. K E Y W O R D S peptibody, peptide-Fc fusion protein, streamlined-expressed protein ligation, sortase-mediated protein ligation, copper-free click chemistry
