Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

Cavaco, Marco; Gaspar, Diana; Castanho, Miguel A. R. B.; Neves, Vera

doi:10.3390/pharmaceutics12010062

Cited by 37 publications

(29 citation statements)

References 124 publications

(138 reference statements)

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“…This process entails binding of the ligand to the receptor, internalization of the ligand–receptor complex, and exocytosis on the abluminal side of the cell [ 3 ]. It is important to keep in mind, however, that high-affinity antibodies toward receptors that mediate RMT will follow the lysosomal pathway when internalized, which results in their degradation [ 22 ]. While this phenomenon creates a challenge in using the RMT mechanism, optimizing the affinity of the ligand that is targeting these receptors has proved to be an effective strategy [ 22 ].…”

Section: Delivery Of Antibodies Into the Brain: Mechanism Of Deliverymentioning

confidence: 99%

Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives

Kouhi

Pachipulusu

Kapenstein

et al. 2021

IJMS

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Due to their high specificity, monoclonal antibodies have been widely investigated for their application in drug delivery to the central nervous system (CNS) for the treatment of neurological diseases such as stroke, Alzheimer’s, and Parkinson’s disease. Research in the past few decades has revealed that one of the biggest challenges in the development of antibodies for drug delivery to the CNS is the presence of blood–brain barrier (BBB), which acts to restrict drug delivery and contributes to the limited uptake (0.1–0.2% of injected dose) of circulating antibodies into the brain. This article reviews the various methods currently used for antibody delivery to the CNS at the preclinical stage of development and the underlying mechanisms of BBB penetration. It also describes efforts to improve or modulate the physicochemical and biochemical properties of antibodies (e.g., charge, Fc receptor binding affinity, and target affinity), to adapt their pharmacokinetics (PK), and to influence their distribution and disposition into the brain. Finally, a distinction is made between approaches that seek to modify BBB permeability and those that use a physiological approach or antibody engineering to increase uptake in the CNS. Although there are currently inherent difficulties in developing safe and efficacious antibodies that will cross the BBB, the future prospects of brain-targeted delivery of antibody-based agents are believed to be excellent.

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Section: Delivery Of Antibodies Into the Brain: Mechanism Of Deliverymentioning

confidence: 99%

Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives

Kouhi

Pachipulusu

Kapenstein

et al. 2021

IJMS

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“…The high demand for mAbs is well-founded, and despite the challenges associated with industrial grade production of homogeneous and efficacious product, they have been used in a number of novel applications [22,23]. Research has suggested mAbs, when combined with BBB peptide shuttles, could penetrate the BBB, and deliver an effective treatment for brain metastases [9]. This could occur through the use of antibody fragments to reduce molecular weight, or the incorporation of cell penetrating peptides (CPPs) into mAbs to deliver large cargoes across cell membranes, and even the BBB [24].…”

Section: Biopharmaceuticalsmentioning

confidence: 99%

“…oral, pulmonary, transdermal), and variation in pharmacokinetic parameters, such as half-life (t 1/2 ), protein binding, and bioavailability. Their comparatively large size means it is unusual for biopharmaceuticals, even small antibody fragments, to cross the blood brain barrier (BBB) [9]. Although this can limit their application to brain disorders, it also means there is reduced risk of unwanted side effects.…”

Section: Introductionmentioning

confidence: 99%

ATR-FTIR spectroscopy and spectroscopic imaging for the analysis of biopharmaceuticals

Tiernan

Byrne

Kazarian

2020

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

138

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Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectroscopy is a label-free, non-destructive technique that can be applied to a vast range of biological applications, from imaging cancer tissues and live cells, to determining protein content and protein secondary structure composition. This review summarises the recent advances in applications of ATR-FTIR spectroscopy to biopharmaceuticals, the application of this technique to biosimilars, and the current uses of FTIR spectroscopy in biopharmaceutical production. We discuss the use of ATR-FTIR spectroscopic imaging to investigate biopharmaceuticals, and finally, give an outlook on the possible future developments and applications of ATR-FTIR spectroscopy and spectroscopic imaging to this field. Throughout the review comparisons will be made between FTIR spectroscopy and alternative analytical techniques, and areas will be identified where FTIR spectroscopy could perhaps offer a better alternative in future studies. This review focuses on the most recent advances in the field of using ATR-FTIR spectroscopy and spectroscopic imaging to characterise and evaluate biopharmaceuticals, both in industrial and academic research based environments.

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“…The brain is a common sanctuary site for SCLC metastases, and patients with CNS metastases typically have a poor prognosis [63]. The blood‐brain barrier limits the delivery of chemotherapy and ICIs to CNS disease, although T cells can more effectively cross, highlighting a potential role for ICIs in CNS metastases [64–66]. As accrual was limited to ECOG PS ≤1 patients and those with treated and or stable/asymptomatic CNS disease, relatively few patients with CNS metastases were accrued to IMpower 133 [37], CASPIAN [40], or KEYNOTE‐604 [48] (8.5%─14.5%, Table 4) compared with actual clinical practice (15%–20%) [67].…”

Section: Discussionmentioning

confidence: 99%

Prolonging Survival: The Role of Immune Checkpoint Inhibitors in the Treatment of Extensive-Stage Small Cell Lung Cancer

et al. 2020

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Background Small cell lung cancer (SCLC) represents approximately 15% of lung cancers, and approximately 70% are diagnosed as extensive‐stage SCLC (ES‐SCLC). Although ES‐SCLC is highly responsive to chemotherapy, patients typically progress rapidly, and there is an urgent need for new therapies. Immune checkpoint inhibitors (ICIs) have recently been investigated in SCLC, and this review provides guidance on the use of these agents in ES‐SCLC based on phase III evidence. Methods Published and presented literature on phase III data addressing use of ICIs in ES‐SCLC was identified using the key search terms “small cell lung cancer” AND “checkpoint inhibitors” (OR respective aliases). Directed searches of eligible studies were periodically performed to ensure capture of the most recent data. Results Six phase III trials were identified, with four assessing the benefits of ICIs plus chemotherapy first‐line, one evaluating ICIs as first‐line therapy maintenance, and one assessing ICI monotherapy after progression on platinum‐based chemotherapy. The addition of ipilimumab or tremelimumab to first‐line treatment or as first‐line maintenance did not improve survival. Two out of three studies combining PD‐1/PD‐L1 inhibitors with first‐line platinum‐based chemotherapy demonstrated significant long‐lasting survival benefits and improved quality of life with no unexpected safety concerns. PD‐1/PD‐L1 inhibitors as first‐line maintenance or in later lines of therapy did not improve survival. Biomarker research is ongoing as well as research into the role of ICIs in combination with radiation therapy in limited‐stage SCLC. Conclusion The addition of atezolizumab or durvalumab to first‐line platinum‐based chemotherapy for ES‐SCLC prolongs survival and improves quality of life. Implications for Practice Platinum‐based chemotherapy has been standard of care for extensive‐stage small cell lung cancer (ES‐SCLC) for more than a decade. Six recent phase III trials investigating immune checkpoint inhibitors (ICIs) have clarified the role of these agents in this setting. Although ICIs were assessed first‐line, as first‐line maintenance, and in later lines of therapy, the additions of atezolizumab or durvalumab to first‐line platinum‐based chemotherapy were the only interventions that significantly improved overall survival and increased quality of life. These combinations should therefore be considered standard therapy for first‐line ES‐SCLC. Biomarker research and investigations into the role of ICIs for limited‐stage disease are ongoing.

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Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

Cited by 37 publications

References 124 publications

Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives

Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives

ATR-FTIR spectroscopy and spectroscopic imaging for the analysis of biopharmaceuticals

Prolonging Survival: The Role of Immune Checkpoint Inhibitors in the Treatment of Extensive-Stage Small Cell Lung Cancer

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