Arming antibodies: prospects and challenges for immunoconjugates

Abstract

Immunoconjugates--monoclonal antibodies (mAbs) coupled to highly toxic agents, including radioisotopes and toxic drugs (ineffective when administered systemically alone)--are becoming a significant component of anticancer treatments. By combining the exquisite targeting specificity of mAbs with the enhanced tumor-killing power of toxic effector molecules, immunoconjugates permit sensitive discrimination between target and normal tissue, resulting in fewer toxic side effects than most conventional chemotherapeutic drugs. Two radioimmunoconjugates, ibritumomab tiuxetan (Zevalin) and tositumomab-131I (Bexxar), and one drug conjugate, gemtuzumab ozogamicin (Mylotarg), are now on the market. For the next generation of immunoconjugates, advances in protein engineering will permit greater control of mAb targeting, clearance and pharmacokinetics, resulting in significantly improved delivery to tumors of radioisotopes and potent anticancer drugs. Pre-targeting strategies, which separate the two functions of antibody-based localization and delivery or generation of the toxic agent into two steps, also promise to afford superior tumor targeting and therapeutic efficacy. Several challenges in optimizing immunoconjugates remain, however, including poor intratumoral mAb uptake, normal tissue conjugate exposure and issues surrounding drug potency and conditional release from mAb carriers. Nonetheless, highly promising results from preclinical models will continue to drive the clinical development of this therapeutic class.

Influence of the Linker on the Biodistribution and Catabolism of Actinium-225 Self-Immolative Tumor-Targeted Isotope Generators

“…The three alpha-emitting daughters of 225 Ac pose a potential threat to injected patients if the elements can not be controlled and cleared quickly. Strategies to decrease exposure to RICs of non-target organs include antibody engineering, pretargeting, extracorporeal depletion, and cleavable conjugates (25). In this article, we describe the design of a self-immolative tumor-targeted isotope nanogenerator.…”

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

“…Radiolabeled antibodies have been used to image a variety of targets, but their slow clearance from the bloodstream and tissue results in limited image contrast. Recent advances in antibody engineering 18,19 have led to the development of several antibody fragment formats that demonstrate excellent properties for targeted PET imaging in animals ( Figure 2A). Translation of modified antibodies for use in the clinic is likely to follow in the near future.…”

Les immunoconjugués, anticorps « armés » pour combattre le cancer

“…Les anticorps armés d'une drogue de chimiothérapie (antibody-drug conjugates ou ADC en anglais) composent, avec les radio-immunoconjugués et les immunotoxines, la classe d'agents thérapeutiques très prometteuse des immunoconjugués [1,2] (➜). Dans les trois cas, l'objectif est identique : il s'agit d'utiliser la spécificité d'un anticorps pour cibler la cellule tumorale et libérer à l'intérieur ou à proximité de celle-ci, un composé hautement toxique qui lui est couplé, comme un agent cytotoxique, un agent radioactif ou une toxine (Figure 1).…”