Integration of monoclonal antibodies and immunoconjugates into the treatment of acute myeloid leukemia
CURRENT OPINION IN HEMATOLOGY
Authors: Amadori, Sergio; Stasi, Roberto
Purpose of review This review addresses use of monoclonal antibodies and Immunoconjugates to treat acute myeloid leukemia. Recent findings Monoclonal antibodies used in acute myeloid leukemia have been directed against the antigens CD33, CD45, and CD66. Unconjugated monoclonal antibodies such as lintuzumab have modest activity against overt acute myeloid leukemia but can eliminate minimal residual disease in acute promyelocytic leukemia. Most experience with immunoconjugates is with gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody linked to the potent antitumor antibiotic calicheamicin. Gemtuzumab ozogamicin has shown activity both singly, particularly in acute promyelocytic leukemia, and combined with conventional cytotoxic chemotherapy. Radiolabeled monoclonal antibodies against CD45 and CD66 have also been used to intensify the conditioning regimen before stem cell transplantation. The most promising results were obtained with radiolabeled anti-CD45 antibodies. Antibodies reactive with CD66 have been used to deliver targeted radiation to hematopoietic tissues in patients with advanced myeloid malignancies. Summary Both unlabeled monoclonal antibodies and immunoconjugates appear to have a limited role if used as single agents to treat acute myeloid leukemia. These agents hold promise as potentially useful additions to conventional therapy, but the optimal dosing and timing remain to be defined.
Targeted cancer therapy: Conferring specificity to cytotoxic drugs
ACCOUNTS OF CHEMICAL RESEARCH
Authors: Chari, Ravi V. J.
The therapeutic activity of most anticancer drugs in clinical use is limited by their general toxicity to proliferating cells, including some normal cells. Although, chemists continue to develop novel cytotoxic agents with unique mechanisms of action, many of these compounds still lack tumor selectivity and have not been therapeutically useful. Monoclonal antibodies that bind to specific markers on the surface of tumor cells offer an alternative therapy that is tumor specific and thus less toxic. Although highly selective, very few monoclonal antibodies are therapeutically useful since they only display modest cell killing activity. The linkage of monoclonal antibodies to highly cytotoxic drugs can be viewed as a means of (a) conferring higher tumor selectivity to cytotoxic drugs that are too toxic to be used on their own or (b) conferring cell killing power to monoclonal antibodies that are tumor-specific but not sufficiently cytotoxic. This Account provides a brief history of the development of antibody-drug conjugates and shows how the lessons learned from the first generation of conjugates has guided the development of more effective antitumor agents. The three components of antibody-drug conjugates, that is, the monoclonal anitbody, the cytotoxic drug, and the linker connecting the drug to the antibody, have been methodically studied and optimized. The antimitotic drug maytansine was chosen for use in the targeted delivery approach because of its high in vitro potency. Analogues of maytansine bearing a disulfide substituent that allowed linkage to monoclonal antibodies via disulfide bonds were prepared. These analogues retain the high potency of the parent drug. The stability of the disulfide link in antibody-maytansinoid conjugates was varied by introduction of methyl substituents on the carbon atoms geminal to the disulfide link. The optimized disulfide linker was stable in circulation in vivo. The circulation half-life of the cytotoxic drug was increased from just a few hours for the unconjugated drug to several days for the conjugate. Upon binding of the conjugate to the tumor cell, internalization and lysosomal processing released the potent cytotoxic agent inside the cell. These conjugates displayed high target-specific cytotoxicity in vitro. The antitumor activity of these targeted agents was superior to that of the antibodies alone or the standard anticancer drugs in human tumor xenograft models. Several conjugates from this new class of tumor-targeted anticancer agents are currently undergoing clinical evaluation. The progress made in the targeted delivery approach and initial clinical results opens the door to the future development of highly potent drugs that were too toxic on their own to be therapeutically useful.