Human Antibody Fusion Proteins/Antibody Drug Conjugates in Breast and Ovarian Cancer

Abstract

Considerable research efforts have been dedicated to understanding ovarian and breast cancer mechanisms, but there has been little progress translating the research into effective clinical applications. Hence, personalized/precision medicine has emerged because of its potential to improve the accuracy of tumor targeting and minimize toxicity to normal tissue. Targeted therapy in both breast and ovarian cancer has focused on antibodies, antibody drug conjugates (ADCs), and very recently the introduction of human antibody fusion proteins. Small molecule inhibitors and monoclonal antibodies (mAbs) are used in conjunction with chemotherapeutic drugs as a form of treatment but problems arise from a board expression of the target antigen in healthy tissues. Also, insufficient tumor penetration due to tight binding affinity and macromolecular size of mAbs compromise the efficacy of these ADCs. A more targeted approach is thus needed, and ADCs were designed to meet this need. However, in ADCs the method of conjugation of drug to antibody is >1, altering the structure of the drug which leads to off-target effects. Random conjugation also causes the drug to affect the pharmokinetics and biodistribution of the antibody and may cause nonspecific binding and internalization. Recombinant therapeutic proteins achieve controlled conjugation reactions and combine cytotoxicity and targeting in one molecule. They can also be engineered to extend half-life, stability and mechanism of action, and offer novel delivery routes. SNAP-tag fusion proteins are an example of a theranostic recombinant protein as they provide a unique antibody format to conjugate a variety of benzyl guanine modified labels, e.g. fluorophores and photosensitizers in a 1:1 stoichiometry. On the one hand, SNAP tag fusions can be used to optically image tumors when conjugated to a fluorophore, and on the other hand the recombinant proteins can induce necrosis/apoptosis in the tumor when conjugated to a photosensitizer upon exposure to a changeable wavelength of light. The dual nature of SNAP-tag fusions as both a diagnostic and therapeutic tool reinforces its significant role in cancer treatment in an era of precision medicine.

Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer

“…Our results demonstrated that the fusion proteins enabled targeted delivery of siRNA which was internalized into PSMA+ prostate cancer cells 25. Although, the anti-PSMA scFv-based siRNA delivery platform exhibited several advantages compared to nanoparticles, lipid spheres, or even an exosomal siRNA delivery system, it still had some unavoidable drawbacks, such as easy availability, potential immunogenicity, rapid renal clearance, short circulation half-life, and failure in activating complement system-mediated cellular immunity 26, 27. To overcome these obstacles in the clinical application of siRNA delivery systems, we adopted a fast and reliable method first described by Bäumer et.al 20, 28 and established stable and efficient transfer carriers for siRNA by PSMA dependent, human monoclonal antibody-mediated delivery platform.…”

Novel treatment strategies for patients with HER2‑positive breast cancer who do not benefit from current targeted therapy drugs (Review)

“…Antibody-drug conjugates (ADCs) are constructed by covalently attaching small-molecule toxins to antibodies (85)(86)(87). T-DM1 is a ADCs that has shown significant activity in treating HER2 + BC (86,87).…”

“…T-DM1 is a ADCs that has shown significant activity in treating HER2 + BC (86,87). A new biparatopic ADC was constructed, consisting of the trastuzumab scFv unit, the 39S Fv unit, and AZ13599185, which inhibits microtubule polymerization during mitosis.…”

Antibody Engineering - Tailor-Made Next Generation Antibodies by Molecular Design

“…Koch and Tesar [5] review the concept of bispecific antibodies as effector cell engagers and discuss promising settings for optimal clinical application. Finally, Padayachee and colleagues [6] discuss the potential of antibody drug conjugates and corresponding recombinant antibody fusion proteins in the background of breast cancer.…”