Abstract
We review drug conjugates combining a tumor-selective moiety with a cytotoxic agent as cancer treatments. Currently, antibody-drug conjugates (ADCs) are the most common drug conjugates used clinically as cancer treatments. While providing both efficacy and favorable tolerability, ADCs have limitations due to their size and complexity. Peptides as tumor-targeting carriers in peptide-drug conjugates (PDCs) offer a number of benefits. Melphalan flufenamide (melflufen) is a highly lipophilic PDC that takes a novel approach by utilizing increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside tumor cells. The only other PDC approved currently for clinical use is 177Lu-dotatate, a targeted form of radiotherapy combining a somatostatin analog with a radionuclide. It is approved as a treatment for gastroenteropancreatic neuroendocrine tumors. Results with other PDCs combining synthetic analogs of natural peptide ligands with cytotoxic agents have been mixed. The field of drug conjugates as drug delivery systems for the treatment of cancer continues to advance with the application of new technologies. Melflufen provides a paradigm for rational PDC design, with a targeted mechanism of action and the potential for deepening responses to treatment, maintaining remissions, and eradicating therapy-resistant stem cells.
Highlights
The development of targeted therapies that selectively bind and act through molecules expressed by cancer cells has been a major advancement in the treatment of cancer, as they mediate higher efficacy with enhanced tolerability compared with traditional cytotoxic agents [1]
This review finds that the promise of drug conjugates to provide effective and tolerable targeted drug delivery systems in patients with cancer has been realized
antibody-drug conjugates (ADCs) approved at the current time predominantly for the treatment of hematologic cancers
Summary
The development of targeted therapies that selectively bind and act through molecules expressed by cancer cells has been a major advancement in the treatment of cancer, as they mediate higher efficacy with enhanced tolerability compared with traditional cytotoxic agents [1]. The targeted agent can be designed to inhibit a protein, such as a receptor or enzyme, expressed by the tumor cell and required for tumor cell growth and progression. Another approach is for an effector molecule, such as an antibody-drug conjugate (ADC), bispecific antibody, or chimeric antigen receptor. 177 Lu-dotatate is a peptide receptor radionuclide therapy that is a targeted form of radiotherapy, allowing the delivery of a radionuclide payload directly to tumor cells that are expressing receptors and binding the homing peptide [3]. We briefly cover some selected examples of PDCs currently under clinical development
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