Towards Physiologically and Tightly Regulated Vectored Antibody Therapies

Abstract

Cancers represent highly significant health issues and the options for their treatment are often not efficient to cure the disease. Immunotherapy strategies have been developed to modulate the patient’s immune system in order to eradicate cancerous cells. For instance, passive immunization consists in the administration at high doses of exogenously produced monoclonal antibodies directed either against tumor antigen or against immune checkpoint inhibitors. Its main advantage is that it provides immediate immunity, though during a relatively short period, which consequently requires frequent injections. To circumvent this limitation, several approaches, reviewed here, have emerged to induce in vivo antibody secretion at physiological doses. Gene delivery vectors, such as adenoviral vectors or adeno-associated vectors, have been designed to induce antibody secretion in vivo after in situ cell modification, and have driven significant improvements in several cancer models. However, anti-idiotypic antibodies and escape mutants have been detected, probably because of both the continuous expression of antibodies and their expression by unspecialized cell types. To overcome these hurdles, adoptive transfer of genetically modified B cells that secrete antibodies either constitutively or in a regulated manner have been developed by ex vivo transgene insertion with viral vectors. Recently, with the emergence of gene editing technologies, the endogenous B cell receptor loci of B cells have been modified with the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated endonuclease (Cas-9) system to change their specificity in order to target a given antigen. The expression of the modified BCR gene hence follows the endogenous regulation mechanisms, which may prevent or at least reduce side effects. Although these approaches seem promising for cancer treatments, major questions, such as the persistence and the re-activation potential of these engineered cells, remain to be addressed in clinically relevant animal models before translation to humans.

Passive Immunization Delays Disease Outcome in Gilthead Sea Bream Infected With Enteromyxum leei (Myxozoa), Despite the Moderate Changes in IgM and IgT Repertoire

“…In mammals, passive immunization represents a prophylactic strategy when vaccination is not possible, such as in immunosuppressed or very young individuals. Also, in the case of certain cancers or emerging human diseases, when vaccines or treatments have not yet been developed ( 44 , 45 ). In fish, passive transfer of spAbs by injection has been successful against some infectious diseases, including parasites ( 4 , 5 , 7 ).…”

Topical review on nano-vaccinology: Biochemical promises and key challenges

“…Similar concerns may arise in the application of other nano-carriers or adjuvants used in the vaccine core antigen potentiation. Closely relevant animal models may be devised to carry out the pre-clinical evaluation of such nano-vaccines [ 45 ]. Biologically mediated nanomaterials have been proven as effective carriers of chemotherapeutic and chemoprophylactic agents.…”

The Importance of Nanocarrier Design and Composition for an Efficient Nanoparticle-Mediated Transdermal Vaccination

“…Another relevant characteristic is the manufacturing reproducibility of the nanosystems to comply with the regulatory requirements. Therefore, the improvement of the animal study models used to evaluate the biogenicity of the materials used to constitute nanosystems needs improvement [159]. The costs associated with the production of nanocomposites will continue to be a focus of development.…”