Overcoming Instability of Antibody‐Nanomaterial Conjugates: Next Generation Targeted Nanomedicines Using Bispecific Antibodies

Abstract

Targeted nanomaterials promise improved therapeutic efficacy, however their application in nanomedicine is limited due to complexities associated with protein conjugations to synthetic nanocarriers. A facile method to generate actively targeted nanomaterials is developed and exemplified using polyethylene glycol (PEG)-functional nanostructures coupled to a bispecific antibody (BsAb) with dual specificity for methoxy PEG (mPEG) epitopes and cancer targets such as epidermal growth factor receptor (EGFR). The EGFR-mPEG BsAb binds with high affinity to recombinant EGFR (KD : 1 × 10(-9) m) and hyperbranched polymer (HBP) consisting of mPEG (KD : 10 × 10(-9) m) and demonstrates higher avidity for HBP compared to linear mPEG. The binding of BsAb-HBP bioconjugate to EGFR on MDA-MB-468 cancer cells is investigated in vitro using a fluorescently labeled polymer, and in in vivo xenograft models by small animal optical imaging. The antibody-targeted nanostructures show improved accumulation in tumor cells compared to non-targeted nanomaterials. This demonstrates a facile approach for tuning targeting ligand density on nanomaterials, by modulating surface functionality. Antibody fragments are tethered to the nanomaterial through simple mixing prior to administration to animals, overcoming the extensive procedures encountered for developing targeted nanomedicines.

Overcoming the Blood–Brain Barrier: The Role of Nanomaterials in Treating Neurological Diseases

“…Instead, the dual-binding nature of the BsAbs enabled the formation of strong non-covalent interactions, resulting in a highly stable drug carrier. [475] Ligand density also plays an important role in determining BBB transport efficacy; and although conclusive design parameters have not yet been agreed upon, the general principles for facilitating optimal brain uptake have been established. An individual ligand's affinity to its receptor is typically reduced when conjugated to a NP.…”

Investigation of the Therapeutic Potential of a Synergistic Delivery System through Dual Controlled Release of Camptothecin–Doxorubicin

“…Bispecific EGFR antibody (BsAb) with a specificity for methoxy PEG (mPEG) epitopes (0.76 mg mL −1 ; equimolar ratio HBP:BsAb) was mixed with HBP/DOX/CPT and incubated in phosphate buffered saline at 25 °C for 1 h following a well‐established method. [ 19 ]…”

“…[ 15–18 ] Our group has successfully developed a bispecific antibody (BsAb) which has dual specificity for both methoxy polyethylene glycol (mPEG) epitopes and EGFR. [ 19 ] mPEG‐functional hyperbranched polymers incubated with BsAbs exhibited significant improvement in accumulation in xenograft breast cancer tumors compared to the untargeted polymer. Moreover, the BsAb approach for labelling polymers provides a more convenient method for developing targeted nanomedicines compared to traditional antibody conjugation onto nanoparticles using covalent chemistries, especially when more complex nanomedicines are developed.…”

Approximation of new generation pharmacological enzyme researches to clinical practice

“…Развитие технологий конъюгатов антитело-лекарство опирается на использование коротких связывающих (линкерных) молекул, присоединение к антителу от 3 до 7 молекул лекарства, безопасность получения целевых продуктов [11]. Сложность конъюгирования белков с синтетическими наноносителями может упрощаться использованием полиэтиленгликоль (ПЭГ)-функциональных наноструктур, связанных с биспецифическими антителами [12]. Двойная специфичность этих антител к метокси-ПЭГ-эпитопам и мишеням раковой патологии (как рецептор эпидермального фактора роста) приводит к тому, что они лучше накапливаются опухолевыми клетками в сравнении с ненацеленными наноматериалами.…”