RDC Development for Leukemia

Leukemia, also known as leukaemia, is one kind of blood cancer that usually begins in the bone marrow and results in high numbers of abnormal blood cells which are not fully developed and are called blasts or leukemia cells. Leukemia can be divided into two categories, such as acute leukemia and chronic leukemia depending on the severity and speed of leukemia. As a group of life-threatening malignant disorders of the blood and bone marrow, acute leukemia is relatively prevalent in the adolescent and young adult populations.

Types and Traditional Therapies of Leukemia

Depending on the difficulty of treatment and cure rates, Leukemia can be roughly divided into three categories, such as easy leukemias, moderate leukemia, and difficult leukemias.

Easy Leukemias

Hairy Cell Leukemia can be treated by interferon α, adenosine nucleoside analogs, and newly discovered rituximab, a cluster of differentiation 20.

Acute Promyelocytic Leukemia constitutes 5% to 10% of acute myeloid leukemia induced by the translocation between chromosomes 15 and 17 and the molecular abnormality of the corresponding promyelocytic leukemia/retinoic acid receptor α, which can be treated by daunorubicin, all-trans retinoic acid, and gemtuzumab ozogamicin.

Chronic Myeloid Leukemia is characterized by the translocation of genetic material between the long arms of chromosomes 9 and 22, which can be treated by the first-generation TKI (BCR-ABL1 tyrosine kinase inhibitors) imatinib mesylate, the second-generation, such as dasatinib, bosutinib, and nilotinib, and the third-generation TKI ponatinib.

Moderate leukemia

Chronic Lymphocytic Leukemia is induced by the absence of chromosome 17 or 11 abnormalities and has an unmutated immunoglobulin heavy chain, the standard therapy of which is most supportive or included therapy with alkylating agents, such as chlorambucil and cyclophosphamide, combined with steroids and vincristine.

Acute Lymphocytic Leukemia in both adolescents and young adults can be treated by a hyper-CVAD regimen and novel CD19-CAR-T therapy.

Difficult Leukemias

Acute Myeloid Leukemia (and High-Risk Myelodysplastic Syndrome) have several therapy approaches, including Fms-related tyrosine kinase 3 inhibitors (FLT3), IDH1 (isocitrate dehydrogenase 1)/IDH2 (isocitrate dehydrogenase 2) inhibitors, gemtuzumab ozogamicin combined with novel antibodies targeting CD33 and CD123, and venetoclax as an important B-cell lymphoma 2 (BCL2) inhibitor.

Leukemia Treatment with RDC

The treatment strategy for leukemia may involve some combination of chemotherapy, radiation therapy, targeted therapy, and bone marrow transplant, in addition to supportive care and palliative care as needed. However, patients continue to have inferior outcomes by these commonly used methods. From a therapeutic perspective, RDC (Radionuclide Drug Conjugate) is an exciting novel strategy for enhancing treatment efficacy, and further clinical application has significant potential to improve the outcome of patients with leukemia.

• Targeted Receptor CD30

CD30 is a member of the TNF receptor superfamily, increase expressed on some neoplasms including HD (Hodgkin's Disease), ALCL (Anaplastic Large Cell Lymphoma, mediastinal B cell lymphoma, embryonal carcinoma, seminoma, and mesothelioma, while in normal tissues CD30 is limited to activated T cells, activated B cells, select thymocytes, and some vascular beds, which makes it a promising target for antibody-based therapy. HeFi-1 is the antibody of CD30. The novel RDC composed of ²¹¹At and HeFi-1 may be applied in leukemia therapy. The combination therapy strategy of a single dose of 12 μCi (0.444 MBq) of radiolabeled ²¹¹At-HeFi-1 with four doses of 100 μg of unmodified HeFi-1 provides further improvement in the survival of the mice.

Fig.1 Kaplan–Meier survival plot of the karpas299 leukemia-bearing SCID/NOD mice. (Zhang, M., et al., 2007, Proc Natl Acad Sci U S A)

• Targeted Receptor CD33

CD33 is another biomarker of acute myeloid leukemia. A new RDC consisting of the α-emitting isotope ²²⁵Ac, with a stable chelated condition, conjugated to the anti-CD33 antibody HuM195 is discovered to be applied in leukemia treatment. With excellent efficacy in monkey studies, this new class of RDC may be applied in leukemia treatment in the future.