Intracellular trafficking of new anticancer therapeutics: antibody–drug conjugates

Abstract

Antibody–drug conjugate (ADC) is a milestone in targeted cancer therapy that comprises of monoclonal antibodies chemically linked to cytotoxic drugs. Internalization of ADC takes place via clathrin-mediated endocytosis, caveolae-mediated endocytosis, and pinocytosis. Conjugation strategies, endocytosis and intracellular trafficking optimization, linkers, and drugs chemistry present a great challenge for researchers to eradicate tumor cells successfully. This inventiveness of endocytosis and intracellular trafficking has given considerable momentum recently to develop specific antibodies and ADCs to treat cancer cells. It is significantly advantageous to emphasize the endocytosis and intracellular trafficking pathways efficiently and to design potent engineered conjugates and biological entities to boost efficient therapies enormously for cancer treatment. Current studies illustrate endocytosis and intracellular trafficking of ADC, protein, and linker strategies in unloading and also concisely evaluate practically applicable ADCs.

Considerations for the Design of Antibody-Based Therapeutics

“…61 An additional consideration for ADC antigens is their ability to internalize and thus transfer the antibody and payload into the targeted cell. 63 Ideally, the rate of receptor-mediated internalization (clathrin-or caveolin-mediated) should surpass that of receptor-independent endocytosis so that ADCs are concentrated into antigen-bearing cells. Rates of internalization of naked and conjugated antibodies are often similar, but in some cases, drug attachment alters these kinetics.…”

“…Rates of internalization of naked and conjugated antibodies are often similar, but in some cases, drug attachment alters these kinetics. 63 Affinity of the antibody to the receptor antigen may also affect the rate of ADC internalization, with one study showing faster internalization for ADCs with tighter Ag affinity. 64 While ADC-targeted receptors should internalize efficiently, they should also display minimal shedding from the membrane.…”

Litmus-Body: a Molecularly Targeted Sensor for Cell-Surface pH Measurements

“…More recently, "acid-switched" ADCs that instead shows high affinity for their target at neutral pH can have improved lysosomal trafficking with enhanced payload delivery and cytotoxicity 52 . In either case, Litmusbody may potentially be useful in monitoring the pH-sensitive payload delivery of ADCs, as well as to screen for ADC variants that are better trafficked into compartments of the desired pH for payload delivery 53,54 . Litmus-bodies bind specifically to their epitope of interest and respond to bulk pH change on live cells.…”

Anticuerpos conjugados a fármacos frente a receptores ERBB: nuevas indicaciones y mecanismos de resistencia

“…La eficacia de un ADC está muy ligada a la internalización del anticuerpo dentro de la célula. La endocitosis puede ocurrir por diferentes rutas de internalización, como la CME, la mediada por caveolina-1 (CAV1) y la independiente de clatrina y caveolina, aunque la CME se considera la principal ruta adoptada por varios ADCs (Kalim et al 2017). Recientemente se ha descrito un modelo preclínico de resistencia a T-DM1 en el que la internalización del ADC se produce a través de CAV1 ).…”

“…Una vez obtenidos los diferentes ADCs, se analizó su acción antiproliferativa en varias líneas celulares con diferentes niveles de expresión de los antígenos contra los que están dirigidos los mAbs: TGFα, EGFR y HER2, para anti-hTGFα, A diferencia de lo observado con otros tratamientos previos, la línea celular de ccRCC más sensible resultó ser la Caki-2. Sin embargo, el efecto antiproliferativo de trastuzumab-DM1 en esta línea, considerando que no expresa HER2, sugiere que podría estar internalizando los ADCs de manera inespecífica, posiblemente por un proceso de pinocitosis (Kalim et al 2017).…”