Antibody-Drug Conjugates for Cancer Therapy Hafeez, Umbreen; Parakh, Sagun; Gan, Hui K ...
Molecules (Basel, Switzerland),
10/2020, Letnik:
25, Številka:
20
Journal Article
Recenzirano
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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.
Thymic carcinoid tumours, especially in the context of multiple endocrine neoplasia type 1 (MEN 1), present significant clinical challenges due to their rarity and aggressive nature. This case report ...describes a complex patient with MEN 1, who suffered from multiple manifestations of the disease, including thymic carcinoid. The tumour was initially resected and treated with adjuvant radiotherapy. Due to slow progression over the years, the tumour was treated with two lines of chemotherapy before the patient succumbed to progressive disease. There is currently limited evidence favoring any specific medical treatment for thymic carcinoid.
•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.
Purpose
Limited progress has been made in treating glioblastoma, and we hypothesise that poor concordance between preclinical and clinical efficacy in this disease is a major barrier to drug ...development. We undertook a systematic review to quantify this issue.
Methods
We identified phase I trials (P1Ts) of tumor targeted drugs, subsequent trial results and preceding relevant preclinical data published in adult glioblastoma patients between 2006–2019 via structured searches of EMBASE/MEDLINE/PUBMED. Detailed clinical/preclinical information was extracted. Associations between preclinical and clinical efficacy metrics were determined using appropriate non-parametric statistical tests.
Results
A total of 28 eligible P1Ts were identified, with median ORR of 2.9% (range 0.0–33.3%). Twenty-three (82%) had published relevant preclinical data available. Five (18%) had relevant later phase clinical trial data available. There was overall poor correlation between preclinical and clinical efficacy metrics on univariate testing. However, drugs that had undergone in vivo testing had significantly longer median overall survival (7.9 vs 5.6mo, p = 0.02). Additionally, drugs tested in ≥ 2 biologically-distinct in vivo models (‘multiple models’) had a significantly better median response rate than those tested using only one (‘single model’) or those lacking in vivo data (6.8% vs 1.2% vs. 0.0% respectively, p = 0.027).
Conclusion
Currently used preclinical models poorly predict subsequent activity in P1Ts, and generally over-estimate the anti-tumor activity of these drugs. This underscores the need for better preclinical models to aid the development of novel anti-glioblastoma drugs. Until these become widely available and used, the use of multiple biologically-distinct in vivo models should be strongly encouraged.
Abstract
INTRODUCTION
No drug has improved survival in recurrent glioblastoma despite encouraging activity preclinically. We undertook a systematic review of matched preclinical and Phase 1 trials ...(P1Ts) of targeted agents to investigate potential preclinical predictors of clinical efficacy.
METHODS
We identified all adult glioblastoma monotherapy P1Ts of targeted agents & preceding preclinical data published between 2006–2019 via structured searches of EMBASE/MEDLINE/PUBMED. For preclinical studies, data regarding in vitro models, in vivo models (species, implantation site, cell-line type) and efficacy (growth inhibition, regression rate, survival) were extracted. For P1T, response rate (RR) data were collected as absolute (%) and categorical (RR< 5% vs. RR≥ 5%) variables. Associations were compared by chi-square/Fisher’s exact test, Kruskal-Wallis or Mann-Whitney U testing as appropriate with 2-sided p-values.
RESULTS
We found 28 P1Ts with median RR 2.9% (range 0.0–33.3%) and mOS 8.0mo (range 4.6–13.0mo). Seven (25%) had ‘minimal’ published pre-clinical data (5 missing entirely; 2 in vitro only); 12 (43%) utilised one cell line in vivo (‘single model’ group); and 9 (32%) used 2+ biologically distinct in vivo models (‘orthogonal’ group). There was strong reliance on U87-based cell lines (14/21 (71%)) in the latter groups. None of the variables tested were associated with RR except for use of ‘orthogonal models’. Compared to the ‘orthogonal’ group, the P1T RR rate was lower in ‘single’ and ‘minimal’ groups (6.8% vs 1.2%, p= 0.043 and 6.8% vs 0.0%, p= 0.026 respectively). The frequency of P1T with a RR > 5% was also higher in the ‘orthogonal’ compared to the same two groups (78% vs 20%, p= 0.042 and 78% vs 17%, p= 0.041).
CONCLUSION
The availability of good quality pre-clinical data, especially the use of orthogonal models in vivo, was significantly associated with P1T response rates and warrants further investigation as a minimal threshold of evidence in future drug development.
The importance of ErbB3 receptor tyrosine kinase in cancer progression, primary and acquired drug resistance, has become steadily evident since its discovery in 1989. ErbB3 overexpression in various ...solid organ malignancies is associated with shorter survival of patients. However, initial strategies to therapeutically target ErbB3 have not been rewarding.
Here, we provide an overview of ErbB3 biology in carcinogenesis. We outline the role of ErbB3 as a critical pathway for resistance to other anti-cancer drugs. We focus on emerging clinical data, which will steer the potential future development of ErbB3 directed therapies.
Initial approaches to ErbB3 targeting have been challenging. However, the lack of success of anti-ErbB3 therapies in ongoing clinical trials may relate more to the complex biology of the receptor and challenges with the biomarkers used to date. Furthermore, it seems certain that the expression of the receptor
is necessary but not sufficient for the response to ErbB3 therapies. Emerging data suggest that more sophisticated biomarkers are needed. Nonetheless, it is also likely that ErbB3 therapies may have the most efficacy in combination therapy, and their favorable toxicity profile makes this feasible.
Antibody drug conjugates (ADCs) are now a proven therapeutic class for many cancers, combining highly specific targeting with the potency of high effective payloads. This review summarizes the ...experience with ADCs in brain tumors and examines future paths for their use in these tumors.
This review will cover all the key classes of ADCs which have been tested in primary brain tumors, including commentary on the major trials to date. The efficacy of these trials, as well as their limitations, will put in context of the overall landscape of drug development in brain tumors. Importantly, this review will summarize key learnings and insights from these trials that help provide the basis for rational ways in which these drugs can be effectively and appropriate developed for patients with primary brain tumors.
ADC development in brain tumors has occurred in two major phases to date. Key learnings from previous trials provide a strong rationale for the continued development of these drugs for primary brain tumors. However, the unique biology of these tumors requires development strategies specifically tailored to maximize their optimal development.
Primary and metastatic tumors of the central nervous system present a difficult clinical challenge, and they are a common cause of disease progression and death. For most patients, treatment consists ...primarily of surgery and/or radiotherapy. In recent years, systemic therapies have become available or are under investigation for patients whose tumors are driven by specific genetic alterations, and some of these targeted treatments have been associated with dramatic improvements in extracranial and intracranial disease control and survival. However, the success of other systemic therapies has been hindered by inadequate penetration of the drug into the brain parenchyma. Advances in molecular characterization of oncogenic drivers have led to the identification of new gene fusions driving oncogenesis in some of the most common sources of intracranial tumors. Systemic therapies targeting many of these alterations have been approved recently or are in clinical development, and the ability to penetrate the blood‐brain barrier is now widely recognized as an important property of such drugs. We review this rapidly advancing field with a focus on recently uncovered gene fusions and brain‐penetrant systemic therapies targeting them.
Implications for Practice
Driver gene fusions involving receptor tyrosine kinases have been identified across a wide range of tumor types, including primary central nervous system (CNS) tumors and extracranial solid tumors that are associated with high rates of metastasis to the CNS (e.g., lung, breast, melanoma). This review discusses the systemic therapies that target emerging gene fusions, with a focus on brain‐penetrant agents that will target the intracranial disease and, where present, also extracranial disease.
Primary and metastatic tumors of the central nervous system present a difficult clinical challenge and are a common cause of disease progression and death. Treatment traditionally consists of surgery and/or radiotherapy or stereotactic radiosurgery; however, systemic therapies have become available or are under investigation for patients whose tumors are driven by specific genetic alterations. This article considers this rapidly advancing field with a focus on recently uncovered gene fusions and the brain‐penetrant systemic therapies targeting them.
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