Protein therapeutics and its enabling sister discipline, protein engineering, have emerged since the early 1980s. The first protein therapeutics were recombinant versions of natural proteins. ...Proteins purposefully modified to increase their clinical potential soon followed with enhancements derived from protein or glycoengineering, Fc fusion or conjugation to polyethylene glycol. Antibody-based drugs subsequently arose as the largest and fastest growing class of protein therapeutics. The rationale for developing better protein therapeutics with enhanced efficacy, greater safety, reduced immunogenicity or improved delivery comes from the convergence of clinical, scientific, technological and commercial drivers that have identified unmet needs and provided strategies to address them. Future protein drugs seem likely to be more extensively engineered to improve their performance, e.g., antibodies and Fc fusion proteins with enhanced effector functions or extended half-life. Two old concepts for improving antibodies, namely antibody-drug conjugates and bispecific antibodies, have advanced to the cusp of clinical success. As for newer protein therapeutic platform technologies, several engineered protein scaffolds are in early clinical development and offer differences and some potential advantages over antibodies.
Antibody therapeutics are a large and rapidly expanding drug class providing major health benefits. We provide a snapshot of current antibody therapeutics including their formats, common targets, ...therapeutic areas, and routes of administration. Our focus is on selected emerging directions in antibody design where progress may provide a broad benefit. These topics include enhancing antibodies for cancer, antibody delivery to organs such as the brain, gastrointestinal tract, and lungs, plus antibody developability challenges including immunogenicity risk assessment and mitigation and subcutaneous delivery. Machine learning has the potential, albeit as yet largely unrealized, for a transformative future impact on antibody discovery and engineering.
Antibodies are a rapidly evolving class of drugs with the potential to treat a myriad of human diseases. Technological advances in areas such as protein engineering and drug delivery are enabling the design of antibodies that overcome some of the hurdles previously limiting their use as therapeutics in certain disease or clinical settings. This review highlights the major obstacles that have limited the use of antibodies as drugs and discusses how antibody design is overcoming these problems to unleash their full therapeutic potential.
Antibodies are the most rapidly growing drug class and have a major impact on human health, particularly in oncology, autoimmunity and chronic inflammatory diseases. Many of the best understood and ...most tractable cell surface and secreted targets with known roles in human diseases have been extensively exploited for antibody drug development. In this Review, we focus on emerging and novel mechanisms of action of antibodies and innovative targeting strategies that could extend their therapeutic applications, including antibody-drug conjugates, bispecific antibodies and antibody engineering to facilitate more effective delivery. These strategies could enable the pursuit of difficult to hit, less well-understood or previously undruggable targets - the 'high-hanging fruit'.
•Bispecific antibodies (BsAb) bind 2 distinct antigens or epitopes on the same antigen.•Antibody domain structure has been exploited to make >60 alternative BsAb formats.•2 BsAb are approved for ...therapy and >30 BsAb are in clinical development.•A common clinical application of BsAb is retargeting T cells to kill tumor cells.•Other clinical uses of BsAb include dual blockade of different disease mediators.
Bispecific antibodies are on the cusp of coming of age as therapeutics more than half a century after they were first described. Two bispecific antibodies, catumaxomab (Removab®, anti-EpCAM×anti-CD3) and blinatumomab (Blincyto®, anti-CD19×anti-CD3) are approved for therapy, and >30 additional bispecific antibodies are currently in clinical development. Many of these investigational bispecific antibody drugs are designed to retarget T cells to kill tumor cells, whereas most others are intended to interact with two different disease mediators such as cell surface receptors, soluble ligands and other proteins. The modular architecture of antibodies has been exploited to create more than 60 different bispecific antibody formats. These formats vary in many ways including their molecular weight, number of antigen-binding sites, spatial relationship between different binding sites, valency for each antigen, ability to support secondary immune functions and pharmacokinetic half-life. These diverse formats provide great opportunity to tailor the design of bispecific antibodies to match the proposed mechanisms of action and the intended clinical application.
The development of therapeutic antibodies has evolved over the past decade into a mainstay of therapeutic options for patients with autoimmune and inflammatory diseases. Substantial advances in ...understanding the biology of human diseases have been made and tremendous benefit to patients has been gained with the first generation of therapeutic antibodies. The lessons learnt from these antibodies have provided the foundation for the discovery and development of future therapeutic antibodies. Here we review how key insights obtained from the development of therapeutic antibodies complemented by newer antibody engineering technologies are delivering a second generation of therapeutic antibodies with promise for greater clinical efficacy and safety.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Antibodies constitute the most rapidly growing class of human therapeutics and the second largest class of drugs after vaccines. The generation of potent antibody therapeutics, which I review here, ...is an iterative design process that involves the generation and optimization of antibodies to improve their clinical potential.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A quarter of a century after their advent, monoclonal antibodies have become the most rapidly expanding class of pharmaceuticals for treating a wide variety of human diseases, including cancer. ...Although antibodies have yet to achieve the ultimate goal of curing cancer, many innovative approaches stand poised to improve the efficacy of antibody-based therapies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This paper presents a novel broadband rectenna for ambient wireless energy harvesting over the frequency band from 1.8 to 2.5 GHz. First of all, the characteristics of the ambient radio-frequency ...energy are studied. The results are then used to aid the design of a new rectenna. A novel two-branch impedance matching circuit is introduced to enhance the performance and efficiency of the rectenna at a relatively low ambient input power level. A novel broadband dual-polarized cross-dipole antenna is proposed which has embedded harmonic rejection property and can reject the second and third harmonics to further improve the rectenna efficiency. The measured power sensitivity of this design is down to -35 dBm and the conversion efficiency reaches 55% when the input power to the rectifier is -10 dBm. It is demonstrated that the output power from the proposed rectenna is higher than the other published designs with a similar antenna size under the same ambient condition. The proposed broadband rectenna could be used to power many low-power electronic devices and sensors and found a range of potential applications.
A novel six-band dual circular polarization (CP) rectenna for ambient radio frequency (RF) energy harvesting is presented. Due to the nonlinearity and complex input impedance of the rectifying ...circuit, the design of a multiband and/or broadband rectenna is always challenging and its performance can be easily affected by variation in the input power level and load. Therefore, an improved impedance matching technique is introduced, which is aimed to improve the performance of the rectifier with a varying condition. A broadband dual CP receiving antenna is proposed, which has a very wide bandwidth (from 550 to 2.5 GHz) and a compact size. An annular ring structure and a novel feeding technique are employed in order to reduce the size and improve the antenna performance. As a result, the proposed rectenna is the first design that covers six frequency bands, including part of the digital TV and most cellular mobile and WLAN bands in the U.K., while the optimal load range for a constant conversion efficiency is from 10 to 75 kΩ. The measured results show that the maximum harvested dc power of the rectenna in typical outdoor and indoor environments are 26 and 8 μW, respectively; it can therefore be applied to a range of low-power wireless applications.
Impedance matching networks for nonlinear devices such as amplifiers and rectifiers are normally very challenging to design, particularly for broadband and multiband devices. A novel design concept ...for a broadband high-efficiency rectenna without using matching networks is presented in this paper for the first time. An off-center-fed dipole antenna with relatively high input impedance over a wide frequency band is proposed. The antenna impedance can be tuned to the desired value and directly provides a complex conjugate match to the impedance of a rectifier. The received RF power by the antenna can be delivered to the rectifier efficiently without using impedance matching networks; thus, the proposed rectenna is of a simple structure, low cost, and compact size. In addition, the rectenna can work well under different operating conditions and using different types of rectifying diodes. A rectenna has been designed and made based on this concept. The measured results show that the rectenna is of high power conversion efficiency (more than 60%) in two wide bands, which are 0.9-1.1 and 1.8-2.5 GHz, for mobile, Wi-Fi, and ISM bands. Moreover, by using different diodes, the rectenna can maintain its wide bandwidth and high efficiency over a wide range of input power levels (from 0 to 23 dBm) and load values (from 200 to 2000 Ω). It is, therefore, suitable for high-efficiency wireless power transfer or energy harvesting applications. The proposed rectenna is general and simple in structure without the need for a matching network hence is of great significance for many applications.
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