Advances and challenges in therapeutic monoclonal antibodies drug development

Abstract

The use of serum containing polyclonal antibodies from animals immunized with toxins marked the beginning of the application of antibody-based therapy in late nineteenth century. Advances in basic research led to the development of the hybridoma technology in 1975. Eleven years later, the first therapeutic monoclonal antibody (mAb) was approved, and since then, driven by technological advances, the development of mAbs has played a prominent role in the pharmaceutical industry. In this review, we present the developments to circumvent problems of safety and efficacy arising from the murine origin of the first mAbs and generate structures more similar to human antibodies. As of October 2017, there are 61 mAbs and 11 Fc-fusion proteins in clinical use. An overview of all mAbs currently approved is provided, showing the development of sophisticated mAbs formats that were engineered based on the challenges posed by therapeutic indications, including antibody-drug conjugates (ADC) and glycoengineered mAbs. In the field of immunotherapy, the use of immunomodulators, bispecific mAbs and CAR-T cells are highlighted. As an example of promising therapy to treat infectious diseases, we discuss the generation of neutralizing monoclonal-oligoclonal antibodies obtained from human B cells. Scientific and technological advances represent mAbs successful translation to the clinic.

The wonderful story of monoclonal antibodies

“…Several models were devised to engineer monoclonal antibodies in sufficient amounts, moving from the initial murine ascites model . Some transgenic animals were developed.…”

“…Currently, most of therapeutic monoclonals are thus human IgG1, which recognize the chosen target by their Fab portion and display effector functions through their Fc. The latter include complement binding in complement depending cytotoxicity (CDC) and attachment to Fc receptors (FcR) on phagocytes in antibody‐dependent cellular phagocytosis (ADCP) and on natural killer cells in antibody‐dependent cellular cytotoxicity (ADCC).…”

“…The medical field of application of these immunotherapies is increasing in range and involves hemato‐oncology, solid tumors, hemophilia, coagulation, asthma, hypercholesterolemia, age‐related macular degeneration, chronic inflammatory diseases, diabetes…to cite a few …”

“…Monoclonal antibodies were first used as ascites fluids as men- Several models were devised to engineer monoclonal antibodies in sufficient amounts, moving from the initial murine ascites model. 33,34 Some transgenic animals were developed. The eggs of transgenic hens and the milk of transgenic rabbits or goats have been successfully used.…”

“…Such strategies also were applied to improve the pharmacokinetics of these new drugs, for instance favoring their recycling by interaction with the neonatal Fcn receptor. 38 Currently, most of therapeutic monoclonals are thus human IgG1, 34 have been devised to modulate these interactions and impact on the drug's pharmacokinetics. 39 Another strategy is to generate hybrid IgG2-CH1 (which does not bind complement) and IgG4-CH3-CG3…”