Progress and Challenges in the Design and Clinical Development of Antibodies for Cancer Therapy

Abstract

The remarkable progress in engineering and clinical development of therapeutic antibodies in the last 40 years, after the seminal work by Köhler and Milstein, has led to the approval by the United States Food and Drug Administration (FDA) of 21 antibodies for cancer immunotherapy. We review here these approved antibodies, with emphasis on the methods used for their discovery, engineering, and optimization for therapeutic settings. These methods include antibody engineering via chimerization and humanization of non-human antibodies, as well as selection and further optimization of fully human antibodies isolated from human antibody phage-displayed libraries and immunization of transgenic mice capable of generating human antibodies. These technology platforms have progressively led to the development of therapeutic antibodies with higher human content and, thus, less immunogenicity. We also discuss the genetic engineering approaches that have allowed isotype switching and Fc modifications to modulate effector functions and bioavailability (half-life), which together with the technologies for engineering the Fv fragment, have been pivotal in generating more efficacious and better tolerated therapeutic antibodies to treat cancer.

Preparation, Characterization and Diagnostic Valuation of Two Novel Anti-HPV16 E7 Oncoprotein Monoclonal Antibodies

“…Firstly, they can be developed as diagnostic kits, rapid diagnostic test strips, antibody-based biosensors or immunosensors, or other products that can detect the content of HPV16 E7 oncoprotein in cervical exfoliated cells, some of which may differentiate high-risk from low-risk [37][38][39]. Secondly, the anti-HPV16 E7 protein mAbs can be transformed into human/mouse chimeric antibodies, or humanized antibodies through Fc modifications, which can be used for blocking the carcinogenic effect induced by the E7 oncogenic protein [40][41][42]. Thirdly, HPV16 E7 human/mouse chimeric antibodies, or humanized HPV16 E7 antibodies can be conjugated with anti-cervical cancer drugs or radiolabels to develop radionuclide imaging agents for both the diagnosis and biological missiles for therapy of HPV16-positive neoplasms, including but not limited to, cervical cancers [43,44].…”

Detection of incipient pancreatic cancer with novel tumor-specific antibodies in mouse models

“…The clinical translation of these rat-derived antibodies will require humanization of the antibody Fc and framework regions because of the well-documented immunogenicity of rodent antibodies in humans [39]. Additionally, the immunoPET modality is expensive and not widely available.…”

Engineering Targeting Materials for Therapeutic Cancer Vaccines

“…In addition, antibody-mediated cytotoxic mechanisms can also efficiently control tumor growth (Zahavi et al, 2018) and be harnessed by cancer vaccination (Figure 1B). Particularly, antibodies that specifically bind to cancer cells can trigger their elimination by antibody-mediated cellular cytotoxicity (ADCC), antibody-mediated cellular phagocytosis (ADCP) or complement-dependent cytotoxicity (CDC) (Almagro et al, 2018). To date, such mechanisms have been mostly exploited in passive cancer immunotherapies via the infusion of therapeutic antibodies in patients, rather than in the context of humoralbased cancer vaccines, which aim to activate endogenous host anti-cancer antibody responses (Huijbers and Griffioen, 2017).…”