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.
Highlights
Several potholes mark the winding road leading to the introduction of therapeutic monoclonal antibodies (TMAs) into routine clinical practice
This article will discuss such situations and ask whether Peptide-Drug-Conjugates (PDCs) may be more appropriate alternatives to antibody-drug conjugates (ADCs)? First, we present an overview of the biological aspects of FDA approved TMAs, those used for hematological cancers. (For summaries of the clinical efficacies of these drugs the reader is referred to recent reviews [6,7,8])
TMA in different clinical settings and given that only about 50% of Phase III trials are completed successfully, we can optimistically expect to see at least several newer TMAs receiving regulatory approval for cancer therapy over the one or two years
Summary
Several potholes mark the winding road leading to the introduction of therapeutic monoclonal antibodies (TMAs) into routine clinical practice. Other limiting factors include the accessibility of potentially useful epitopes within a native multi-molecular complex to bulky antibody proteins and the lower antibody binding affinities towards weaker antigens It remains to be seen whether more recent technical improvements aimed at overcoming these variables [80] will yield clinically successful TMAs to novel tumor cell markers. In those studies truncated (single chain variable fragment, scFv) and full length antibody penetration into the tumor mass was inversely related to the antibody affinity and internalization rate of the target antigen These results are counterintuitive to the traditional strategy of developing high affinity antibodies and again highlight the need for a deep understanding of the biology of immunotherapy when selective TMA candidates.
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