Friday, May 9, 2025
5/9/2025
Novel Approaches to CD33-Directed Radioimmunotherapy - ABSTRACT Antigen-specific therapies have long been pursued to improve outcomes in acute myeloid leukemia (AML). Most exploited are monoclonal antibodies (mAbs) targeting the membrane-distal V-set domain of CD33, a glycoprotein displayed on leukemic blasts in almost all cases and possibly leukemia stem cells in some. Improved survival of some patients with gemtuzumab ozogamicin validates this approach but many patients with CD33+ AML do not benefit from this antibody-drug conjugate, prompting interest in developing improved CD33-directed therapeutics. Because AML cells are sensitive to radiation, a-emitting radionuclides are ideal to arm anti-CD33 mAbs. Unlike b-emitters, they deliver a very high amount of radiation over just a few cell diameters to enable precise and efficient target cell kill. Early trials with an anti-CD33 mAb labeled with actinium-225 (225Ac- lintuzumab) have been conducted, but important shortcomings include high costs, long half-life, and release of free daughter radionuclides after decay of 225Ac with risk of non-specific toxicity to healthy tissues. We hypothesize astatine-211 (211At), an a-emitter we have focused on because of its shorter half-life and because it decays without production of any long-lived or potentially dangerous daughter isotopes, will provide a novel, superior payload for CD33-directed radioimmunotherapy (RIT). Using humanized mice, we have generated a panel of fully human mAbs recognizing either the V-set domain or the membrane-proximal C2-set domain of CD33. Since the V-set but not C2-set domain is missing in some CD33 variants, C2-set domain-directed mAbs can recognize all naturally occurring variants of CD33 (i.e., are “CD33PAN mAbs”). With these mAbs available, we now plan to optimize CD33-directed RIT for application in AML patients. To accomplish this task, we have assembled a multidisciplinary team of investigators with complementary expertise in developing radioimmunoconjugates and other mAb-based therapeutics for AML. We will focus our efforts on 2 connected areas of research. In the first, we will identify a candidate mAb clone to be used as basis for the clinical therapeutic, and then employ protein engineering techniques to build a delivery vehicle with minimized/abolished potential to interact with Fc receptors to increase the selectivity of the deposition of radionuclides on CD33+ cells and to minimize off-target toxicities to normal cells. In parallel, we will develop an improved and simplified radionuclide capture technology that could replace the currently used approach of radioconjugation/astatination. We expect our results will define a new form of CD33-RIT that should be readily translatable into the clinic for patients with AML and other CD33+ neoplasms, for whom current treatment outcomes are unsatisfactory.
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