Targeted drug delivery for cancer therapy: the other side of antibodies

Abstract

Therapeutic monoclonal antibody (TMA) based therapies for cancer have advanced significantly over the past two decades both in their molecular sophistication and clinical efficacy. Initial development efforts focused mainly on humanizing the antibody protein to overcome problems of immunogenicity and on expanding of the target antigen repertoire. In parallel to naked TMAs, antibody-drug conjugates (ADCs) have been developed for targeted delivery of potent anti-cancer drugs with the aim of bypassing the morbidity common to conventional chemotherapy. This paper first presents a review of TMAs and ADCs approved for clinical use by the FDA and those in development, focusing on hematological malignancies. Despite advances in these areas, both TMAs and ADCs still carry limitations and we highlight the more important ones including cancer cell specificity, conjugation chemistry, tumor penetration, product heterogeneity and manufacturing issues. In view of the recognized importance of targeted drug delivery strategies for cancer therapy, we discuss the advantages of alternative drug carriers and where these should be applied, focusing on peptide-drug conjugates (PDCs), particularly those discovered through combinatorial peptide libraries. By defining the advantages and disadvantages of naked TMAs, ADCs and PDCs it should be possible to develop a more rational approach to the application of targeted drug delivery strategies in different situations and ultimately, to a broader basket of more effective therapies for cancer patients.

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…Several interesting cytotoxic peptide conjugates are under clinical trials, but none have been approved by FDA for the clinical use, because some issues, like their short half-lives, still have to be solved [49][50][51][52][53][54]. In both antibodies and peptides, the linker of the conjugates should be stable during blood transportation, intra or extracellularly in the target cells by specific enzymatic or chemical degradation, releasing the active cytotoxic agents into the cancer cells [55,56].…”

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“…Traditional Chemotherapy, Radiotherapy and other nonspecific use of therapeutic agents encounter their short comings due to poor specificity and severe side effects which often leads to exacerbation of the situation 37 . Peptidomimetics provides a more target specific approach in dealing with the intricacies of PPIs.…”

Optimizing antibody–drug conjugates for targeted delivery of therapeutics

“…This vision in part became true with the development and approval of therapeutic monoclonal antibodies. However, many therapeutic monoclonal antibodies that showed promise in preclinical studies when used on their own failed in the clinic because of insufficient cancer cell toxicity [1]. To overcome this problem, there has been an exponential growth in the field of antibody-drug conjugates (ADCs), where a monoclonal antibody is linked to a highly cytotoxic drug.…”