Investigational antibody drug conjugates for solid tumors

INTRODUCTION: Despite the progress made in the past 20 years in understanding the molecular events leading to the formation of cancer, the success of targeted antitumor agents in solid tumors has lagged behind the scientific discoveries. The most difficult to treat patient segments are those with refractory solid tumors, resistant to standard chemotherapy, and novel therapeutic compounds with improved therapeutic indexes are needed. Antibody drug conjugates (ADCs) are poised to become an important class of cancer therapeutics, as evidenced by the promising objective response rates when administered as single agents to chemorefractory cancer patients. AREAS COVERED: The basic concept for ADCs is to combine the strengths of the two most successful classes of therapeutic compounds developed in oncology, the high selectivity of antibodies with the unrivaled potency of small molecules, with the goal to improve the therapeutic index. Currently, approximately 60 ADCs are being developed in oncology. Among them, about 20 are undergoing clinical testing, the majority of which are tubulin inhibitor-based immunoconjugates. Herein, we review ADCs targeting solid tumors, with the focus on 11 programs currently undergoing clinical development. EXPERT OPINION: Key challenges the ADC field is facing, including potency and safety, can be addressed effectively by introducing novel research concepts with transformational potential for ADC development.     

Antibody drug conjugates under investigation in phase I and phase II clinical trials for gastrointestinal cancer

ABSTRACT

Introduction: Antibody drug conjugates (ADCs) represent a developing class of anticancer therapeutics which are designed to selectively deliver a cytotoxic payload to tumors, while limiting systemic toxicity to healthy tissues. There are several ADCs which are currently in various stages of clinical development for the treatment of gastrointestinal malignancies.

Areas covered: We discuss the biologic rationale and review the clinical experience with ADCs in the treatment of gastrointestinal malignancies, summarizing the pre-clinical and phase I/II clinical trial data that have been completed or are ongoing.

Expert opinion: While there have been significant advances in the development of ADCs since they were first introduced, several challenges remain. These challenges include (i) the selection of an ideal antigen target which is tumor specific and internalized upon binding, (ii) selection of an antibody which has high affinity for its antigen target and low immunogenicity, (iii) selection of a potent payload which is cytotoxic at sub-nanomolar concentrations, and (iv) optimal design of a linker to confer ADC stability with limited off-site toxicity. Efforts are ongoing to address these issues and innovate the ADC technology to improve the safety and efficacy of these agents.     

First platinum(II)-based metal-organic linker technology (Lx®) for a plug-and-play development of antibody-drug conjugates (ADCs)

ABSTRACT

Introduction: Compared to the antibody and drug components of an ADC, the linker part has been somewhat neglected. However, its importance for the reduction of failures in ADC approvals is increasingly recognized. Next of being a stable glue between drug and antibody, an ideal linker should improve the manufacturability and widen the therapeutic window of ADCs.

Areas covered: The biopharmaceutical company LinXis started an ADC development program in which platinum(II) is the key element of the first metal-organic linker. The cationic complex [ethylenediamineplatinum(II)]²⁺, herein called ‘Lx®’, is used successfully for conjugation of drugs to antibodies.

Expert opinion: Based on lessons learned from ADC development, Lx linker technology fulfills most of the desirable linker characteristics. Lx allows large-scale cost-effective manufacturing of ADCs via a straightforward two-step ‘plug-and-play’ process. First clinical candidate trastuzumab-Lx-auristatin F shows favorable preclinical safety as well as outstanding in vivo tumor targeting performance and therapeutic efficacy.     

The potential of neurotrophic tyrosine kinase (NTRK) inhibitors for treating lung cancer

Introduction: Molecular alterations in neurotrophic tyrosine kinase (NTRK) genes have been identified in several solid tumors including lung cancer. Pre-clinical and clinical evidence suggested their potential role as oncogenic drivers and predictive biomarkers for targeted inhibition, leading to the clinical development of a new class of compounds blocking the NTRK molecular pathway, which are currently undner early clinical investigation.

Area covered: This review describes the biology of the NTRK pathway and its molecular alterations in lung cancer. It focuses on the pre-clinical and clinical development of emerging NTRK inhibitors, which have shown very promising activity in early phase I studies.

Expert opinion: Among the several NTRK-inhibitors, entrectinib and LOXO-101 are those in more advanced stage of clinical development. Both agents have shown encouraging activity along with a tolerable safety profile in patients with different solid tumors harboring NTRK-fusions, emerging as new promising therapeutic options for molecularly selected patients with advanced Trk-driven lung cancers. Results from ongoing phase II basket trials are eagerly awaited.     

Recent advances in targeting the fatty acid biosynthetic pathway using fatty acid synthase inhibitors

ABSTRACT

Introduction: Elevated lipogenesis has been associated with a variety of diseases including obesity, cancer and nonalcoholic fatty liver disease (NAFLD). Fatty acid synthase (FASN) plays a pivotal role in de novo lipogenesis, making this multi-catalytic protein an attractive target for therapeutic intervention. Recently, the first FASN inhibitor successfully advanced through the drug development process and entered clinical evaluation in oncology.

Areas covered: This review discusses the biological roles of FASN in three prominent disease areas: cancer, obesity-related disorders and NAFLD. Recent advances in drug discovery strategies and design of newer FASN inhibitors are also highlighted.

Expert opinion: Despite the abundance of evidence linking the lipogenic pathway to cancer, progression of FASN-targeted molecules has been rather slow and challenging and no compounds have moved past the preclinical phase. The landscape has recently changed with the recent advancement of the first FASN inhibitor into clinical evaluation for solid tumors. Needless to say, the successful translation into the clinical setting will open opportunities for expanding the therapeutic utility of FASN inhibitors not just in oncology but in other diseases associated with elevated lipogenesis such as obesity, type 2 diabetes, and NAFLD.     

Advances in stem cells,induced pluripotent stem cells,and engineered cells: delivery vehicles for anti-glioma therapy

Introduction: A limitation of small molecule inhibitors, nanoparticles (NPs) and therapeutic adenoviruses is their incomplete distribution within the entirety of solid tumors such as malignant gliomas. Currently, cell-based carriers are making their way into the clinical setting as they offer the potential to selectively deliver many types of therapies to cancer cells.

Areas covered: Here, we review the properties of stem cells, induced pluripotent stem cells and engineered cells that possess the tumor-tropic behavior necessary to serve as cell carriers. We also report on the different types of therapeutic agents that have been delivered to tumors by these cell carriers, including: i) therapeutic genes; ii) oncolytic viruses; iii) NPs; and iv) antibodies. The current challenges and future promises of cell-based drug delivery are also discussed.

Expert opinion: While the emergence of stem cell-mediated therapy has resulted in promising preclinical results and a human clinical trial utilizing this approach is currently underway, there is still a need to optimize these delivery platforms. By improving the loading of therapeutic agents into stem cells and enhancing their migratory ability and persistence, significant improvements in targeted cancer therapy may be achieved.     

Novel dual Src/Abl inhibitors for hematologic and solid malignancies

Importance of the field: c-Src and Bcr-Abl are two non-receptor or cytoplasmic tyrosine kinases (TKs) that play important roles in the development of solid and hematological malignancies. Indeed, Src is overexpressed or hyperactivated in a variety of solid tumors, while Bcr-Abl is the causative agent of chronic myeloid leukemia (CML), where Src is also involved. The two enzymes share significant sequence homology and remarkable structural resemblance.

Areas covered in this review: ATP-competitive compounds originally developed as Src inhibitors, showed to be also potent Abl inhibitors. Dasatinib, the first dual Src/Abl inhibitor approved by the US FDA in 2006 for the treatment of imatinib-resistant CML, is currently being tested in several clinical trials for the treatment of different solid tumors. SKI-606 and AZD0530 are two other important dual Src/Abl inhibitors extensively tested in animal models and in clinical trials, but not entered into therapy yet.

What the reader will gain: In this review we will report the latest results regarding dasatinib, SKI-606 and AZD0530, but also the knowledge on new compounds that have appeared in the literature in the last few years, including AP24163, AP24534, XL228, DC2036. We will focus on the most recent clinical trials or on preclinical studies that are in progress on these small-molecule TK inhibitors that represent a targeted therapy with high potential against cancer.

Take home message: Molecularly targeted therapies, including the inhibition of specific TKs hyperactivated or overexpressed in many human cancers, could be less toxic than the classical non-specific cytotoxic chemotherapeutic agents; they could offer important therapeutic effects, especially if used in association with other agents such as monoclonal antibodies.     

Emerging formats for next-generation antibody drug conjugates

Introduction: Antibody drug conjugates now make up a significant fraction of biopharma’s oncology pipeline due to great advances in the understanding of the three key components and how they should be optimised together. With this clinical success comes innovation to produce new enabling technologies that can deliver more effective antibody-drug conjugates (ADCs) with a larger therapeutic index.

Areas covered: There are many reviews that discuss the various strategies for ADCs design but the last 5 years or so have witnessed the emergence of a number of different antibody formats compete with the standard whole immunoglobulin. Using published research, patent applications and conference disclosures, the authors review the many antibody and antibody-like formats, discussing innovations in protein engineering and how these new formats impact on the conjugation strategy and ultimately the performance. The alternative chemistries that are now available offer new linkages, stability profiles, drug:antibody ratio, pharmacokinetics and efficacy. The different sizes being considered promise to address issues, such as tumour penetration, circulatory half-life and side-effects.

Expert opinion: ADCs are at the beginning of the next stage in their evolution and as these newer formats are developed and examined in the clinic, we will discover if the predicted features have a clinical benefit. From the commercial activity, it is envisaged that smaller or fragment-based ADCs will expand oncological applications.     

Methylselenocysteine – a promising antiangiogenic agent for overcoming drug delivery barriers in solid malignancies for therapeutic synergy with anticancer drugs

Introduction: Despite progress, chemotherapeutic response in solid malignancies has remained limited. Although initial results of the use of antiangiogenic agents in combination chemotherapy indicated an enhanced therapeutic response, recent data indicate that the surviving cancer is not only able to surmount therapy, but also actually able to adapt a more aggressive metastatic phenotype. Thus, selecting an antiangiogenic agent that is less likely to lead to tumor resurgence is a key to future therapeutic success of antiangiogenic agents in a combinatorial setting.

Areas covered: Against the broad spectrum of antiangiogenic agents used at present in the clinic, the putative benefits of the use of organoselenium compounds, such as methylselenocysteine (MSC), are discussed in this review.

Expert opinion: MSC, being part of the mammalian physiology, is a well-tolerated, versatile and economical antiangiogenic agent. It downregulates multiple key upstream tumor survival markers, and enhances tumor drug delivery, at a given systemic dose of an anticancer agent, while protecting normal tissue from cytotoxic adverse effects. Further clinical trials, especially in poorly differentiated cancers, are warranted.     

Antifolate agents: a patent review (2006 – 2010)

Introduction: For > 50 years, drugs targeting the folate pathway have significantly impacted disease treatment as anticancer, antimicrobial and immunomodulatory agents. The discovery of novel antifolate agents with improved properties and superior activities remains an attractive strategy, both in academia and the pharmaceutical industry.

Areas covered: This review surveys the patent literature from 2006 to 2010 for small molecule inhibitors of enzymatic targets in the folate biosynthetic pathway.

Expert opinion: The pursuit of antifolates as anticancer and antimicrobial agents continues to be an active area of research. New patent disclosures reveal novel antifolate scaffolds, antifolates with improved drug-like properties and new strategies to effectively target cancer cells. The continued use of high resolution structural information has guided the discovery of several compounds. Owing to the need for high levels of potency and selectivity, especially in targeting pathogenic species, the use of high resolution crystal structures remains an important tool to guide the design of novel antifolates. Interestingly, the patents disclosing novel compounds were ones where X-ray crystallography was an integral component of the design process. Finally, a variety of new structures have been reported that may play an important role in the future development of therapeutic antifolates.     

The development of pyrrolobenzodiazepines as antitumour agents

Introduction: DNA interacting agents play a major role in cancer chemotherapy, either as single agents, in combination drug regimens, or as components of novel targeted therapies. The search for more selective and efficacious drugs that can deliver critical DNA damage with minimal side effects continues.

Areas covered: The development of the pyrrolobenzodiazepines (PBDs) from their discovery as natural products in the 1960s, through synthetic PBD monomers, PBD hybrids and conjugates, and PBD dimers is described. The latter molecules are capable of forming sequence selective, non-distorting and potently cytotoxic DNA interstrand cross-links in the minor groove of DNA. In particular, the development of PBD dimer SJG-136 (SG2000), currently in Phase II clinical trials, is presented. Potential future cancer therapeutic applications of PBDs, including their use as components of targeting strategies, are also discussed.

Expert opinion: The culmination of over four decades of study on structure–activity relationships of PBDs has led to a detailed understanding of how to introduce structural modification to enhance biological activity and potency. The challenge for the next phase in the development of the PBDs is to harness this activity and potency in a new generation of cancer therapeutics.     

New perspectives of valproic acid in clinical practice

Introduction: Valproic acid (VPA) has been used in clinical practice as an anticonvulsant for more than four decades. Its pharmacokinetics and toxicity are thus well documented. VPA is also a potent class-selective histone deacetylase (HDAC) inhibitor at nontoxic therapeutic concentrations. New areas of application for VPA are currently opening up in clinical practice.

Areas covered: The authors discuss VPA and how it may serve as an effective drug for cancer therapy. This is due to its ability to induce differentiation of a number of cancer cells in vitro and also to decrease tumor growth and metastases in animal models. The authors highlight how the utilization of VPA as an HDAC inhibitor is not limited to a single-agent therapy. Early clinical studies have also revealed promising potency of VPA in combination treatment with classic anticancer drugs. The authors do this by summarizing the published results and providing insight into the potential future developments for this field.

Expert opinion: VPA was shown to restore or improve responsiveness of tumors to conventional therapeutic agents, to enhance the efficacy of adenoviral gene therapy, to sensitize TRAIL-resistant tumor cells to apoptosis, and to enhance radiosensitivity of tumor cells. Drawbacks in VPA medical applications include its teratogenicity and complexity of its effects.     

抗体药物偶联物（ADC）药动学研究的认识

抗体药物偶联物（ADC）是由具有靶向特异性的单抗和具有高毒性的小分子结合而成的新药,与单抗和小分子药物相比,具有特异性高和毒性低的特征。由于这种特性,用于ADC的药动学（PK）研究的生物分析方法>的建立和选择具有挑战性。同时大分子抗体和小分子组分的药物,生物分析方法的组合对了解ADC的体外与体内过程,认识药物运送到作用部位和暴露反应关系十分重要。因此,对ADC的开发策略、新生物分析方法的开发、建立和验证,以及临床前和临床PK、PK/PD研究的问题的挑战和机遇必须有足够认识。就ADC的药动学研究的进展和难点予以介绍,以期与从事该类药物的研究者一起讨论和分析。     

Update on non-viral delivery methods for cancer therapy: possibilities of a drug delivery system with anticancer activities beyond delivery as a new therapeutic tool

Importance of the field: Cancer is the most formidable human disease. Owing to the heterogeneity of cancer, a single-treatment modality is insufficient for the complete elimination of cancer cells. Therapeutic strategies from various aspects are needed for cancer therapy. These therapeutic agents should be carefully selected to enhance multiple therapeutic pathways. Non-viral delivery methods have been utilized to enhance the tumor-selective delivery of therapeutic molecules, including proteins, synthetic oligonucleotides, small compounds and genes.

Areas covered in this review: As non-viral delivery methods, liposomes and polymer-based delivery materials to target tumors mainly by systemic delivery, physical methods including electroporation, sonoporation, and so on, to locally inject therapeutic molecules, and virosomes to use the viral infectious machinery for the delivery of therapeutic molecules are summarized.

What the reader will gain: This article aims to provide an overview of the characteristic properties of each non-viral vector. It will be beneficial to utilize appropriately the vector for cancer treatment.

Take home message: Efficient and minimally invasive vectors are generally considered to be the ideal drug delivery system (DDS). However, against cancer, DDS equipped with antitumor activities may be a therapeutic choice. By combining therapeutic molecules with DDS having antitumor activities, enhancement of the multiple therapeutic pathways may be achieved.     

Carbonic anhydrase inhibition as a cancer therapy: a review of patent literature, 2007 – 2009

Importance of the field: The functional contribution of membrane-bound extracellular carbonic anhydrases (CAs) to hypoxic tumor growth and progression has long been hypothesized; however, recent convergent evidence from a number of groups strongly implicates these CAs as key prosurvival enzymes during tumor hypoxia. From this perspective targeting the inhibition of cancer-associated CA enzymes, most notably CA IX and XII, has recently been identified as a mechanistically novel scientific opportunity with great potential as a new cancer drug target.

Areas covered in this review: This review covers world patent applications filed during the 2007 – 2009 period for small molecule approaches; non-small molecule approaches are not within the scope of this review.

What the reader will gain: The reader will be provided with a background of the biology of CAs as well as the recent research findings that have validated the crucial prosurvival role of CAs in hypoxic tumors. The review will highlight small molecule molecular methods that modulate CAs as an anti-cancer therapeutic strategy.

Take home message: Much of what has been reported in the patent literature during the period 2007 – 2009 is based on alleged therapeutic benefits of CA inhibitors in cancer. Recently appropriate CA-relevant cell and animal models of tumor hypoxia for the evaluation of compounds have become available and the verification of the ability of small molecules to modulate CA activity as a cancer therapy or as a diagnostic and/or prognostic tool is now possible and probable. The CA field will thus provide for a scientifically exciting and possibly rewarding next few years, accelerated by the growing interest in the potential clinical applications of this enzyme class in oncology.     

Chemotherapy regimens and treatment protocols for laryngeal cancer

Importance of the field: Laryngeal cancer has been the model of curative-intent organ-preserving therapies in clinical oncology. Although the optimal care of patients with laryngeal cancer is truly multidisciplinary, with progressive advances in surgical, radiation, and medical oncology, the development of effective systemic therapies has been a major component of the therapeutic arsenal against laryngeal cancer.

Areas covered in this review: This review will discuss the rapidly evolving roles of chemotherapy in the management of locally advanced and metastatic laryngeal cancer.

What the reader will gain: The reader will gain a historical perspective on this evolution in treatment and will appreciate current treatment challenges and promising future directions in optimizing therapeutic efficacy in functional larynx preservation and in patient survival.

Take home message: The treatment of most patients with laryngeal cancer with systemic therapy represents an opportunity to positively impact functional outcomes with an anatomically and functionally preserved larynx. Future challenges include identification of novel therapies and optimizing therapy protocols for individualized patient care.     

Research and innovation in the development of everolimus for oncology

Introduction: The critical role of increased activity of mammalian target of rapamycin (mTOR) in the pathophysiology of multiple diseases is well established. Inhibition of the mTOR pathway may block disease progression and improve patient outcomes. Everolimus, an mTOR inhibitor, began in clinical development as part of a regimen (Certican, Zortress) for prevention of organ transplant rejection and is now an approved oncology agent.

Areas covered: The objective of this review is to discuss the history of key findings and innovative cancer research undertaken to successfully develop everolimus as an oncology therapy (Afinitor) now approved for patients with advanced renal cell carcinoma (RCC) and for subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis. In addition, data for the use of everolimus in the treatment of other cancers and rare diseases are also discussed. A PubMed search of English articles without time restrictions was conducted using the search terms ‘everolimus or rapamycin’ and ‘cancer’. Bibliographies of retrieved articles were manually searched for additional relevant articles. Major cancer congresses were also searched.

Expert opinion: The clinical efficacy of everolimus alone and in combination with other agents has been observed in recently completed Phase II–III studies in a wide spectrum of tumors, including RCC, neuroendocrine tumors, tuberous sclerosis complex, SEGAs and angiomyolipomas, lymphoma and gastric, breast and hepatocellular cancers. These findings emphasize the importance of mTOR in diverse cancers and rare diseases and underscore the potential role for everolimus as an effective agent in multiple indications.     

Metallic nanoparticles: technology overview & drug delivery applications in oncology

Importance of the field: The targeted delivery of therapeutic agents to tumour cells is a challenge because most of the chemotherapeutic agents distribute to the whole body, which results in general toxicity and poor acceptance by patients and sometimes discontinuation of the treatment. Metallic nanoparticles have been used for a huge number of applications in various areas of medical treatment. Metallic nanoparticles are emerging as new carrier and contrast agents in cancer treatment. These metallic nanoparticles have been used for imaging of tumour cells by means of active and passive targeting. Recent advances have opened the way to site-specific targeting and drug delivery by these nanoparticles.

Areas covered in this review: This review summarizes the mechanisms of passive and active targeted drug delivery by metallic nanoparticles and their potential use in cancer theranostics.

What the reader will gain: The reader will gain information on the development of tumour cells, advantages of modern methods of cancer treatment over the traditional method, targeted delivery of anticancer agents using nanoparticles, influence of nanotechnology on the quality and expectancy of life, and challenges, implications and future prospects of metallic nanoparticles as probes in cancer treatment.

Take home message: The development of metallic nanoparticles is rapid and multidirectional, and the improved practical potential of metallic nanoparticle highlights their potency as new tools for future cancer therapeutics modalities.     

Talaporfin sodium

Importance of the field: Despite therapeutic advances, cancer remains the cause of an estimated 23% of deaths in the USA. New treatments for malignancy are greatly needed.

Areas covered in this review: Talaporfin sodium is a light-activated drug that causes tissue death through induction of apoptosis. Systemic antitumor effects mediated by CD8⁺ T cells have been demonstrated in preclinical studies, providing a mechanism for distant response of tumors noted in clinical trials. Talaporfin sodium is approved in Japan for early-stage endobronchial cancer. Phase I and II studies in solid tumors have shown tumor regression in patients refractory to other therapies. Phase III pivotal studies against hepatocellular carcinoma as monotherapy and liver-metastatic colorectal cancer in combination with chemotherapy are ongoing. Talaporfin sodium is also in studies in men with symptomatic benign prostatic hyperplasia. Substantial safety data from clinical trials so far indicate that the drug is well tolerated.

What the reader will gain: Talaporfin sodium has a broad safety profile and a mode of action that could affect growth in treated and untreated tumors.

Take home message: Clinical and preclinical studies indicate that talaporfin sodium treatment may offer a powerful option to synergize current therapies, as well as an alternative monotherapy in treating cancer.