Cure of Disseminated Human Lymphoma with [Ac]Ac-Ofatumumab in a Preclinical Model.

in Journal of nuclear medicine : official publication, Society of Nuclear Medicine by Mark S Longtine, Kyuhwan Shim, Mark J Hoegger, Nadia Benabdallah, Diane S Abou, Daniel L J Thorek, Richard L Wahl

TLDR

  • Researchers developed a new treatment that uses an antibody to target and kill cancer cells in mice with lymphoma.
  • The treatment, [Ac]Ac-ofatumumab, is highly effective in prolonging survival and is a potential new therapy for human lymphoma patients.

Abstract

Immunotherapies that target the CD20 protein expressed on most non-Hodgkin lymphoma cells have improved clinical outcomes, but relapse is common. We preparedAc-labeled anti-CD20 ofatumumab and evaluated its in vitro characteristics and therapeutic efficacy in a murine model of disseminated human lymphoma.Ac was chelated by DOTA-ofatumumab, and radiochemical yield, purity, immunoreactivity, stability, and chelate number were determined. In vitro cell killing of CD20-positive, human B-cell lymphoma Raji-Luc cells was assayed. Biodistribution was determined as percentage injected activity per gram (%IA/g) in mice with subcutaneous Raji-cell tumors (= 4). [Ac]Ac-ofatumumab biodistribution in C57BL/6N mice was performed to estimate projected human dosimetry. Therapeutic efficacy was tested in mice with systemically disseminated Raji-Luc cells, tracking survival, bioluminescence, and animal weight for a targeted 200 d, with single-dose therapy initiated 8, 12, or 16 d after cell injection, comparing no treatment, ofatumumab, and low (3.7 kBq/mouse) and high (9.25 kBq/mouse) doses of [Ac]Ac-IgG and [Ac]Ac-ofatumumab (= 8-10/cohort).Radiochemical yield and purity were 32% ± 9% and more than 95%, respectively. Specific activity was more than 5 MBq/mg. Immunoreactivity was preserved, and more than 90% of theAc remained chelated after 10 d in serum. Raji-Luc cell killing in vitro was significant, specific, and dose-dependent. In tumor-bearing mice, [Ac]Ac-ofatumumab displayed low liver (7 %IA/g) and high tumor (28 %IA/g) uptake. Dosimetry estimates indicated that bone marrow is likely the dose-limiting organ. When therapy was initiated 8 d after cell injection, untreated mice and mice treated with cold ofatumumab or low- or high-dose [Ac]Ac-IgG showed indistinguishable median survivals of 20-24 d, with extensive cancer-cell burden before death. Low- and high-dose [Ac]Ac-ofatumumab profoundly (< 0.05) extended median survival to 190 d and more than 200 d (median not determinable), with 5 and 9 of 10 mice, respectively, surviving at study termination with no detectable cancer cells. Surviving mice treated with high-dose [Ac]Ac-ofatumumab showed reduced weight gain versus naïve mice. When therapy was initiated 12 d, but not 16 d, after cell injection, high-dose [Ac]Ac-ofatumumab significantly extended median survival to 40 d but was not curative.In an aggressive disseminated tumor model, [Ac]Ac-ofatumumab was effective at cancer-cell killing and curative when administered 8 d after cell injection. [Ac]Ac-ofatumumab has substantial potential for clinical translation as a next-generation therapeutic for treatment of patients with non-Hodgkin lymphoma.

Overview

  • The study evaluates the characteristics and therapeutic efficacy of Ac-labeled anti-CD20 ofatumumab in a murine model of disseminated human lymphoma.
  • The study uses Ac-ofatumumab, a novel radioimmunotherapeutic agent, to target the CD20 protein expressed on most non-Hodgkin lymphoma cells.
  • The primary objective is to test the therapeutic efficacy of [Ac]Ac-ofatumumab in mice with systemically disseminated Raji-Luc cells.

Comparative Analysis & Findings

  • The study finds that low- and high-dose [Ac]Ac-ofatumumab significantly extends median survival in mice with disseminated lymphoma, with 5 and 9 out of 10 mice, respectively, surviving at study termination with no detectable cancer cells.
  • The therapeutic efficacy of [Ac]Ac-ofatumumab was observed when therapy was initiated 8 d after cell injection, with no detectable cancer cells in surviving mice.
  • The study also finds that high-dose [Ac]Ac-ofatumumab reduces weight gain in surviving mice compared to naïve mice.

Implications and Future Directions

  • The study has substantial potential for clinical translation as a next-generation therapeutic for treatment of patients with non-Hodgkin lymphoma.
  • Future studies could investigate the optimal dosing and timing of therapy to maximize efficacy and minimize side effects.
  • The study highlights the importance of considering biodistribution and dosimetry estimates in radioimmunotherapeutic agents to avoid dose-limiting organs.
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