Rational and clinical development of the anti-MAdCAM monoclonal antibody for the treatment of IBD

Introduction: Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression in gut-associated lymphoid tissue is upregulated in patients with inflammatory bowel disease (IBD). Blocking adhesion molecules and thereby inhibiting migration of lymphocytes into sites of inflammation in the gut is an attractive new treatment target in drug development for IBD.

Areas covered: This review discusses the preclinical and clinical experience on SHP647 (previously called PF-00547659 and PF-00547,659), a fully human IgG2K monoclonal antibody that binds to MAdCAM-1 to selectively reduce lymphocyte homing to the intestinal tract.

Expert opinion: Blocking endothelial adhesion molecule MAdCAM?1 could represent an attractive target for the treatment of IBD. In the next years, the results from the phase III studies as well as data to support therapeutic drug monitoring based on drug levels to guide and optimize individual therapy will become available. Furthermore, much effort is put in the development of clinical prediction models to predict which drug is optimal for an individual patient.

Trial registration: ClinicalTrials.gov identifier: NCT03259334.

Trial registration: ClinicalTrials.gov identifier: NCT03259308.

Trial registration: ClinicalTrials.gov identifier: NCT03559517.

Trial registration: ClinicalTrials.gov identifier: NCT03566823.

Trial registration: ClinicalTrials.gov identifier: NCT01298492.     

Developments in liposomal gene delivery systems

ABSTRACT

Introduction: Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology. Currently approved therapies include prednisone, TNF antagonists and anti-metabolites which often are ineffective and have frequent adverse effects. Consequently, UC patients are always at risk for developing serious complications that affect their quality of life. Therefore, new treatment options are required.

Areas covered: This article discusses etrolizumab, its mechanism and the potential role it can have in the future of treating UC. Etrolizumab is a humanized monoclonal antibody that selectively blocks lymphocyte trafficking and retention in the gut. The safety and efficacy data was reviewed from all randomized placebo-controlled trials which evaluated etrolizumab for the treatment of UC.

Expert opinion: Etrolizumab is an effective and well-tolerated drug for the treatment of UC. It appears to be a promising molecule that can benefit UC patients.     

Positioning ustekinumab in moderate-to-severe ulcerative colitis: new kid on the block

ABSTRACT

Introduction: Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract. Dysregulated innate and adaptive immune pathways contribute to intestinal inflammation in IBD, and cytokines, including IL-12 and IL-23, play a key role. The blockade of both IL-12 and IL-23 may have an impact on different pathways of inflammation and could be effective for the treatment of inflammatory bowel diseases.

Ustekinumab is a fully human IgG1κ monoclonal antibody which binds to the shared p40 protein subunit of IL-12 and ?23. It is currently approved for several immune-mediated diseases such as moderate to severe plaque psoriasis, psoriatic arthritis, and Crohn’s disease, and has shown promising results in UC.

Areas covered: A review of the literature was performed to understand several aspects including the role of IL-12 and ?23 in UC, the potential therapeutic role of ustekinumab in inflammatory bowel disease, and the positioning of ustekinumab in the therapeutic algorithm of UC, based on extrapolated data from available randomized clinical trials.

Expert opinion: Ustekinumab is effective and safe in UC, and shows potential advantages compared to other drugs in moderate-to-severe UC.     

Anti-EGFR and antiangiogenic monoclonal antibodies in metastatic non-small-cell lung cancer

ABSTRACT

Introduction: In recent years, several clinical trials have evaluated the efficacy and safety of biological therapies in lung cancer. Epidermal growth factor receptor (EGFR) and the axis vascular endothelial growth factor receptor (VEGF/VEGFR) are targeted by small molecules and monoclonal antibodies (mAbs), especially in non-squamous non-small-cell lung cancer (NSCLC).

Areas covered: The current state of the art of anti-EGFR and antiangiogenic monoclonal antibodies in metastatic NSCLC is reviewed and discussed.

Expert opinion: Bevacizumab and cetuximab are the most studied mAbs in NSCLC, but only bevacizumab is in clinical practice in the first-line setting. Necitumumab is a new anti-EGFR monoclonal antibody that improves survival when combined to cisplatin/gemcitabine chemotherapy and has been approved in first-line advanced NSCLC. Ramucirumab, an antiangiogenic drug binding with high affinity to VEGFR-2, improves the results of chemotherapy alone when administered with docetaxel and has been approved in second-line setting. Moreover, the novel combination of bevacizumab and erlotinib is very promising for the treatment of patients with NSCLC harbouring EGFR mutations. The association of antiangiogenic mAbs and immunotherapy is under investigation too.     

Anti-interleukin-23 agents for the treatment of ulcerative colitis

ABSTRACT

Introduction: Treatment of ulcerative colitis (UC) aims to control symptoms and to suppress intestinal inflammation. Despite considerable advances, a proportion of patients do not respond to currently available drugs. The interleukin (IL)-23 axis plays a significant role in the pathogenesis of UC and has thus become an important target for drug development.

Areas covered: The review briefly summarizes the pathophysiology of the IL-12/23 axis and provides a synopsis of the available evidence for efficacy and safety of ustekinumab, mirikizumab (LY3074828), risankizumab (BI655066/ABBV066), brazikumab (MEDI2070; formerly AMG139) and guselkumab (CNTO1959) in UC. We also provide an overview of ongoing and anticipated trials in this field.

Expert opinion: A Phase 2 trial with mirikizumab and a Phase 3 trial with ustekinumab have demonstrated the efficacy of anti-IL-23 agents in achieving clinical and endoscopic outcomes in UC with a favorable safety profile. Trials of other anti-IL-23 agents in UC are under way and designed to explore head-to-head efficacy with existing biologics, as well as the prospect of combination biological therapy. Apart from data on longer term efficacy and safety, future trials should also explore strategies to inform the positioning of IL-23 antagonists in therapeutic algorithms.     

Adecatumumab: an anti-EpCAM monoclonal antibody,from the bench to the bedside

Importance of the field: In developing new anticancer drugs, the identification of relevant targets is a key issue of growing importance. Ideally, an anticancer drug target should be specific to cancer cells, in order to both increase efficacy and decrease toxicity of the compound.

Areas covered in this review: Epithelial cell adhesion molecule (EpCAM) is a membrane protein with proto-oncogenic properties that is expressed in a number of endothelium-derived cancers and is a promising anticancer drug target. Adecatumumab is a monoclonal, fully human IgG1 antibody that targets EpCAM, development of which is at present reaching Phase III trials.

What the reader will gain: From a review of literature, we here update the rationale for using EpCAM as an anticancer target for monoclonal antibodies, with a special focus on adecatumumab. The fully human nature of adecatumumab is also discussed to put the drug in perspective with other related anti-EpCAM monoclonal antibodies, such as edrecolomab and catumaxomab. Adecatumumab studies are recapitulated, in order to provide the reader with a comprehensive view of the development of this promising anticancer agent.

Take home message: Adecatumumab is a promising fully human monoclonal antibody targeting EpCAM which is expressed in almost all adenocarcinomas and its activity is not dependent of K-Ras status.     

Pembrolizumab for the treatment of diffuse large B-cell lymphoma

ABSTRACT

Introduction: Pembrolizumab is a novel monoclonal antibody that targets the interaction between programmed cell death protein 1 (PD-1) and its ligand (PD-L1). Pembrolizumab has shown significant clinical efficacy in Hodgkin Lymphoma (HL), but results in non Hodgkin Lymphoma (NHL) are mixed. Some NHL subtypes, which share certain genetic features with HL, such as alterations in chromosome 9p24.1 and expression of PD-L1, have shown promising responses in early phase trials.

Areas covered: In this review, we provide an overview of pembrolizumab as a compound, and present the available clinical efficacy and safety data in the treatment of diffuse large B cell lymphomas.

Expert opinion: Current early phase data suggest that single agent pembrolizumab in NHL demonstrates both efficacy and a favorable safety profile. However, it is anticipated that future treatment strategies will be biomarker-driven and incorporate pembrolizumab into combination therapies with chemotherapy and/or immunotherapy agents.     

Efficacy and safety of otelixizumab use in new-onset type 1 diabetes mellitus

ABSTRACT

Introduction: Type 1 diabetes (T1DM) is an immune-mediated disease induced by antigen-specific T cells infiltrating pancreatic beta cells leading to the progressive loss of endogenous insulin secretion.

Areas covered: The identification of specific components of the autoimmune response favoured the implementation of several immunomodulatory therapies including antiCD3 monoclonal antibody (mAb) called otelixizumab. Otelixizumab is a chimeric monoclonal antibody that targets the ε-chain of the CD3T-lymphocyte surface receptor that has been developed with the aim of short therapeutic courses capable of inducing a remission of T1DM. Clinical trials have been carried out with otelixizumab to evaluate its safety and efficacy, but despite positive results of Phase I and II studies, the results of Phase III studies have been contradictory.

Expert opinion: High doses of otelixizumab have shown beneficial effects on beta cell function whereas a lower dose, which was tested to avoid the adverse effects associated with higher doses, was not effective on beta cells preservation. We believe that otelixizumab is a drug of potential interest for treating new onset T1DM patients and its use in combination with other immunomodulatory agents should be considered as a solution to circumvent adverse effects while maintaining efficacy.     

Infliximab biosimilar CT-P13 therapy is effective in maintaining endoscopic remission in ulcerative colitis – results from multicenter observational cohort

ABSTRACT

Background: CT-P13, the first biosimilar monoclonal antibody to infliximab (IFX), has previously been confirmed to be efficacious in inducing mucosal healing in ulcerative colitis (UC) patients. The aim of this study was to evaluate the efficacy of CT-P13 therapy in maintaining mucosal healing in UC.

Methods: CT-P13 trough levels, antibody positivity, serum inflammatory markers as CRP level, fecal calprotectin at weeks 14 and 54, concomitant steroid and azathioprine therapy at the time of induction therapy and at weeks 14 and 54, previous use of anti TNF drug and the need of dose intensification as possible predictive factors for mucosal healing at week 54 were evaluated in this prospective study.

Results: 61 patients had already completed the 54-week treatment period. Mucosal healing was shown in 65.5 % and 62.1 %, complete mucosal healing was present in 31% and 38 % at week 14 and 54, respectively. The median values of CRP, leukocytes, thrombocytes, and albumin showed significant difference between baseline and week 54. Serum antibody positivity was proved in 6.5 % and 19.7 % of cases at week 14 and 54, respectively.

Conclusion: Our study confirmed the long-term efficacy of CT-P13 therapy on mucosal healing in UC.     

Vedolizumab and etrolizumab for ulcerative colitis: twins or simple cousins?

ABSTRACT

Introduction: Vedolizumab is a monoclonal antibody that selectively blocks α4β7 integrin and has already been approved for use in patients with moderate-to-severe ulcerative colitis both as first and second line. Etrolizumab is a monoclonal antibody still being tested, which acts with a dual mechanism by selectively inhibiting both α4β7 and αEβ7 integrins.

Areas covered: This review provides an overview of the literature data of vedolizumab and etrolizumab, in order to define their role in the treatment of patients with moderate-to-severe ulcerative colitis.

Expert opinion: Etrolizumab and vedolizumab block the α4β7 integrin with a similar action mechanism. However, the inhibition of αEβ7 integrin by etrolizumab distinguishes the two anti-integrins making them ‘cousin’ drugs. Phase 3 clinical trials are needed to confirm the promising etrolizumab’s efficacy data and to resolve any doubts about its safety, allowing a clearer comparison with vedolizumab.     

Amelioration of murine experimental colitis by inhibition of mucosal addressin cell adhesion molecule-1

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is an adhesion molecule that mediates recruitment of lymphocytes into the gut mucosa. Attenuation of excessive expression of MAdCAM-1 in the inflamed mucosa could be useful for treatment of inflammatory bowel diseases. The aim of this study was to investigate whether anti-MAdCAM-1 antibody has a prophylactic effect on experimental colitis induced by dextran sulfate sodium (DSS). Colitis was induced by orally feeding BALB/c mice 5% DSS (mol. wt. 5000). Mice were sacrificed at intervals up to 21 days after administration to evaluate the changes over time in intestinal damage. The infiltrating lymphocytes and their subpopulations, and the expression of cell adhesion molecules were determined by immunohistochemistry. In another set of experiments, the attenuating effect of i.p.-injected anti-MAdCAM-1 antibody on colonic lesions was evaluated on day 14. Significant histological damage with shortening of crypts was observed on day 14 in colonic mucosa of DSS-treated mice. Before mucosal inflammation had become significant, expression of MAdCAM-1 was already increased in the microvessels of lamina propria on day 7. Significant infiltration of beta7-integrin-positive T and B cells in the mucosa was then noted on day 14. Administration of anti-MAdCAM-1 antibody significantly reduced colonic injury as well as the infiltration of beta7-integrin-positive lymphocytes in the colonic mucosa. This antibody also was effective when given 7 days after the start of DSS treatment. In the present study, we demonstrated that anti-MAdCAM-1 antibody significantly ameliorates DSS-induced colitis, suggesting that MAdCAM-1 may be useful for control of inflammatory bowel diseases.     

Infliximab biosimilar CT-P13 therapy is effective and safe in maintaining remission in Crohn’s disease and ulcerative colitis – experiences from a single center

Background: CT-P13, the first biosimilar monoclonal antibody to infliximab (IFX), has been confirmed to be efficacious in inducing remission in inflammatory bowel diseases (IBD). The aim of this study was to evaluate the long-term efficacy and safety of CT-P13 therapy in Crohn’s disease (CD) and ulcerative colitis (UC), and to identify predictors of sustained clinical response during a 54-week CT-P13 treatment period.

Patients and methods: Patients with CD and UC, who were administered CT-P13, were prospectively enrolled. Clinical response was assessed at week 14 and week 54. Predictive factors for disease outcome at week 54 were evaluated.

Results: 57 CD and 57 UC patients were included; 55 CD and 49 UC patients completed the induction therapy and 50 CD and 46 UC patients completed the 54-week treatment period. Clinical remission was achieved in 65.5% of CD and 75.5% of UC patients at week 14. Rate of continuous clinical response was 51% in both CD and UC at week 54. None of the examined parameters were predictive to the clinical outcome neither in CD, nor in UC.

Conclusion: This study confirmed the long-term efficacy and safety of CT-P13 therapy in IBD. Response rates at week 54 were similar in CD and UC.     

Which place for avelumab in the management of urothelial carcinoma?

Introduction: Urothelial carcinoma (UC) has a poor prognosis, with the only standard first-line metastatic treatment being platinum-based chemotherapy. Until 2018, there was no Food and Drug Administration (FDA)-approved drug for second-line setting, and only vinflunine was approved by the European Medicines Agency (EMEA) in Europe. However, targeting the programmed cell-death 1 (PD-1)/PD-ligand 1 (PD-L1) pathway with immune checkpoint inhibitor (ICI) agents has shown encouraging results. Avelumab is a human anti-PD-L1 antibody that is currently being investigated in several trials.

Areas covered: In this review article, we summarise preclinical, clinical, and safety data on avelumab for UC, and describeongoing trials that are evaluating avelumab for local or advanced diseases. We also compare its place in the management of UC.

Expert opinion: Avelumab has shown clinical efficacy for metastatic and advanced UC in phase I studies after the failure of platinum-based therapy with a well-tolerated safety profile. This anti-PD-L1 targeting agent has the capacity to induce antibody-dependant cellular cytotoxicity (ADCC)-mediated tumor cell lysis compared to other ICI. These results led to FDA approval of avelumab as a second-line treatment for locally advanced and metastatic UC. Avelumab is also investigated in phase II and in a randomized phase III trial as a maintenance therapy in UC as well for combination use with chemotherapy.     

Otelixizumab: a novel agent for the prevention of type 1 diabetes mellitus

Introduction: Type 1 diabetes mellitus is a chronic, progressive autoimmune disorder linked to numerous genetic and environmental factors. Insulin is the only treatment and preventative strategies do not currently exist. An obvious need exists to develop a safe regimen that suppresses the progression of the disease.

Areas covered: A MEDLINE search (1966–June 2011) was conducted for English-language articles using the terms ‘otelixizumab’, ‘anti-CD3 antibody’ and ‘prevention of type 1 diabetes mellitus’. Relevant literature on otelixizumab, an anti-CD3 monoclonal antibody, currently in Phase III clinical trials for prevention of T1DM is discussed.

Expert opinion: Studies suggest that a monoclonal antibody directed against CD3 mitigates the deterioration in insulin production and decreases the rise in insulin requirement in recent onset T1DM for up to five years. The benefit was most pronounced in younger patients and in those with higher initial β-cell function. Adverse effects were significant but transient. Otelixizumab shows great promise but leaves room for improvement. Results of ongoing trials will help define its role in the prevention of T1DM.     

New biologic therapeutics for ulcerative colitis and Crohn's disease

Introduction: Some inflammatory bowel disease (IBD) patients especially those with refractory Crohn's disease (CD) or relapsing ulcerative colitis (UC) do not respond to current therapies. The newly introduced biological drugs have got some interest due to their specificity and selectivity in modulation of inflammatory elements.

Areas covered: In 46 included randomized, placebo-controlled clinical trials, the efficacy and safety of different biologic drugs have been evaluated in moderately to severely active CD or UC patients. Current investigated drugs include new anti-TNF drugs (adalimumab, certolizumab pegol, etanercept, onercept and golimumab), anti-CD20 (rituximab), T-cell inhibitors (abatacept) and anti-α4 integrins (natalizumab and vedolizumab). Adalimumab, certolizumab, and golimumab showed significant efficacy in induction of remission and maintenance in CD and UC patients with a rate of adverse events similar to placebo in the major trials. Natalizumab and vedolizumab were effective in the treatment of moderately to severely active CD and UC patients. However, vedolizumab caused less adverse effects than natalizumab. onercept, etanercept, rituximab and abatacept were all well tolerated but were not effective in CD or UC patients.

Expert opinion: Anti-TNF drugs, except for onercept and etanercept, and anti-α4 integrins exhibit beneficial therapeutic effects. Although they were all well tolerated, the incidence of progressive multifocal leukoencephalopathy associated with natalizumab should not be missed.     

The prospect of patritumab for treating non-small cell lung cancer

ABSTRACT

Introduction: The mutation or expression of HER family members serves as a therapeutic target for tyrosine kinase inhibitors or monoclonal antibodies in diverse cancers, such as non-small cell lung cancer, breast cancer, gastric cancer, head and neck cancer, colorectal cancer, pancreatic cancer and glioblastoma. HER3, which heterodimerizes with HER1 and HER2, has received much attention as a potential target for anti-EGFR treatment. Patritumab is a novel, fully human monoclonal antibody directed against HER3.

Areas covered: In this review article, an overview of the market, chemistry, pharmacodynamics, pharmacokinetics, efficacy, and safety of patritumab is provided based on data from phase I studies, a combination phase I trial, and a randomized phase II trial comparing two doses of patritumab.

Expert opinion: The combination of patritumab plus erlotinib has shown a promising efficacy and safety in early-phase clinical trials. In a randomized phase II trial, higher mRNA expression of heregulin (a ligand of HER3) was associated with better progression-free survival and a tendency toward improved overall survival. In the era of precise treatment based on an appropriate target with a predictive biomarker, further studies with patritumab are needed to realize its potential in cancer treatment.     

Lebrikizumab in the treatment of asthma

ABSTRACT

Introduction: Severe asthma continues to be a major clinical problem despite the availability of effective asthma medications such as inhaled corticosteroids. Several targeted biologic therapies are emerging to treat patients with severe asthma.

Areas covered: This review provides an update of information on lebrikizumab, a novel monoclonal antibody that targets IL-13 and is currently in advanced stages of development. It describes the role of IL-13, a key effector cytokine in Type 2 (T2) airway inflammation in asthma and discusses the results of recent phase 2 trials investigating lebrikizumab’s efficacy and safety in patients with severe asthma. Furthermore, it provides insight into the current ongoing trials with lebrikizumab and outlines future research needs.

Expert opinion: Several emerging therapeutic targets have been identified for patients with severe asthma. By specifically targeting IL-13, lebrikizumab has the potential to block several downstream signals that play a role in disease progression including airway inflammation, mucus hypersecretion and airway remodeling. The effects of lebrikizumab have been more marked in individuals with high serum periostin levels which reflect underlying IL-13 activity and T2 airway inflammation. Ongoing trials with lebrikizumab aim to further examine its long-term safety and efficacy in a larger population and explore its effects on airway inflammation and function.     

The evolving role of monoclonal antibodies in the treatment of patients with advanced renal cell carcinoma: a systematic review

ABSTRACT

Introduction: While the majority of the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors currently used for the therapy of metastatic renal cell carcinoma (mRCC) are small molecule agents inhibiting multiple targets, monoclonal antibodies are inhibitors of specific targets, which may decrease off-target effects while preserving on-target activity. A few monoclonal antibodies have already been approved for mRCC (bevacizumab, nivolumab), while many others may play an important role in the therapeutic scenario of mRCC.

Areas covered: This review describes emerging monoclonal antibodies for treating RCC. Currently, bevacizumab, a VEGF monoclonal antibody, is approved in combination with interferon for the therapy of metastatic RCC, while nivolumab, a Programmed Death (PD)-1 inhibitor, is approved following prior VEGF inhibitor treatment. Other PD-1 and PD-ligand (L)-1 inhibitors are undergoing clinical development.

Expert opinion: Combinations of inhibitors of the PD1/PD-L1 axis with VEGF inhibitors or cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors have shown promising efficacy in mRCC. The development of biomarkers predictive for benefit and rational tolerable combinations are both important pillars of research to improve outcomes in RCC.