Monoclonal antibody drug conjugates in the treatment of cancer

Abstract

Monoclonal antibodies directed to tumor-associated antigens have been chemically conjugated to drugs with different mechanisms of action and different levels of potency. Monoclonal-antibody-directed drug delivery has the potential to both improve efficacy and reduce systemic toxicity. Several immunoconjugates have demonstrated impressive antigen-specific antitumor activity in preclinical models. Phase I trials of a calicheamicin immunoconjugate for treatment of acute myeloid leukemia and a doxorubicin immunoconjugate for treatment of carcinoma have recently been completed.

Introduction

The treatment of cancer is limited by a number of factors including the low therapeutic index of most chemotherapeutic agents, the emergence of drug- and radiation-resistant populations, tumor heterogeneity and the presence of metastatic disease. One of the means to improve the therapeutic index of drugs is by selective or ‘targeted’ delivery to tumor sites. Tumor-directed therapy has the potential to improve efficacy, by increasing the intratumoral concentration of the targeted agent, and to minimize toxicity by reducing systemic exposure. Monoclonal antibodies (MAbs), MAb fragments, hormones and growth factors have been used to deliver drugs, toxins, radionuclides, enzymes, photosensitizers and cytokines to tumors.

Unfortunately, the clinical efficacy of MAb-directed therapy is frequently limited by expression of the targeted antigen on normal as well as malignant cells. With the exception of MAbs to idiotypic domains of lymphocytes, truly tumor-specific MAbs have not been identified; rather, MAbs identify tumor-associated antigens expressed at higher density on malignant cells relative to normal cells. It is therefore necessary to balance the relative selectivity of the MAb with the potency of the agent delivered. Studies in preclinical models with human tumors in immunodeficient mice have demonstrated impressive activity for many of these conjugates. However, it is important to recognize that these models, while useful, frequently over-predict activity and under-predict toxicity because the antigen targeted is tumor-specific in the mouse but tumor-associated in patients. Nevertheless, several immunoconjugates have shown impressive activity even though the targeted antigen is expressed on normal tissues of immunodeficient animals or normal tissues of immunocompetent animals bearing syngeneic tumors 1, 2, 3•.

Significant progress has been made for MAb-directed therapies in the treatment of patients who have lymphoma 4, 5••. In addition, the use of the MAb 17-1A following tumor resection has resulted in improved survival of patients with Dukes’ C colorectal cancer [6^•] and improved response rates were seen in breast cancer patients receiving the anti-HER2 MAb, directed against the HER2 transmembrane tyrosine-kinase receptor coded by the HER2 gene (also known as neu and as c-erbB-2), in combination with cisplatin [7]. However, only occasional responses have been reported for MAbs or immunoconjugates used as monotherapy in the treatment of patients with advanced solid tumors. The physical barriers of solid tumors — including elevated interstitial pressure, heterogeneous and reduced functional vasculature and the relatively large distances for MAbs to travel in the tumor interstitium [8^•] — contribute to the limited tumor penetration and minimal efficacy seen when MAb-directed therapies are used as single agents in patients with advanced disease.

Several modifications have been used to improve the efficacy of immunoconjugate therapy. Immunogenicity has been reduced by using chimeric [9^••] or humanized [5^••] MAbs. Attempts to decrease the amount of MAb needed for antitumor activity have included the use of more potent drugs 3•, 10 and alternative strategies such as branched linkers [11^•] and delivery of liposome-encapsulated drugs 12, 13•, 14 to increase the quantity of drug delivered per antibody molecule. Improved MAb distribution in solid tumors has been addressed by using pharmacological approaches to improve penetration [15]. Recent studies have demonstrated that directing therapy to antigens expressed on the tumor vasculature (a readily accessible compartment), rather than to tumor-associated antigens of solid tumors, can produce impressive activity in preclinical models 16, 17•, 18••, 19, 20. This review will concentrate on the results of recent clinical trials of MAb–drug immunoconjugates and highlight current strategies to improve the potency, specificity and efficacy of immunoconjugate therapy.