Pre-Clinical Evaluation of a 213Bi-Labeled 2556 Antibody to HIV-1 gp41 Glycoprotein in HIV-1 Mouse Models as a Reagent for HIV Eradication

Any strategy for curing HIV infection must include a method to eliminate viral-infected cells. Based on our earlier proof-of-principle results targeting HIV-1 infected cells with radiolabeled antibody (mAb) to gp41 viral antigen, we embarked on identifying a suitable candidate mAb for preclinical development.Among the several human mAbs to gp41 tested, mAb 2556 was found to have high affinity, reactivity with multimeric forms of gp41 present on both the surface of virus particles and cells expressing HIV-1 Env, and recognition of a highly conserved epitope of gp41 shared by all HIV-1 subtypes. Also, mAb 2556 was the best in competition with HIV-1+ serum antibodies, which is an extremely important consideration for efficacy in the treatment of HIV patients. When radiolabeled with alpha-emitting radionuclide 213-Bismuth ((213)Bi) - (213)Bi-2556 efficiently and specifically killed ACH-2 human lymphocytes chronically infected with HIV-1, and HIV-1 infected human peripheral blood mononuclear cells (hPBMCs). The number of binding sites for (213)Bi-2556 on the surface of the infected cells was >10(6). The in vivo experiments were performed in two HIV-1 mouse models--splenic and intraperitoneal. In both models, the decrease in HIV-1 infected hPBMCs from the spleens and peritoneum, respectively, was dose-dependent with the most pronounced killing of hPBMCs observed in the 100 µCi (213)Bi-2556 group (P = 0.01). Measurement of the blood platelet counts and gross pathology of the treated mice demonstrated the lack of toxicity for (213)Bi-2556.We describe the preclinical development of a novel radiolabeled mAb reagent that could potentially be part of an HIV eradication strategy that is ready for translation into the clinic as the next step in its development. As viral antigens are very different from "self" human antigens - this approach promises high selectivity, increased efficacy and low toxicity, especially in comparison to immunotoxins

NPM1 and FLT3-TKD mutations are enriched in patients with leukemia cutis

Leukemia cutis (LC) is a dermatologic manifestation of leukemia. Its clinical implications for the patient and the biological mechanism behind the manifestation of LC are unknown. The oncology community is increasingly utilizing mutations to classify a number of malignancies to prognosticate outcomes and to choose targeted therapies. A single-center, retrospective analysis of dermatopathology cases with a diagnosis of leukemia cutis was performed. Patients with genetic testing using the Columbia Combined Cancer Panel (a targeted sequencing protocol of 467 genes) or Genoptix (targeted sequencing protocol of 44 genes) were identified. The frequency of the presence of genetic mutations in LC patients was compared to AML patients from the COSMIC (Catalogue of Somatic Mutations in Cancer) database. Twenty nine cases were confirmed to have leukemia cutis, 22 of which had acute myeloid leukemia (AML). Genetic testing was available in 11 patients. Twelve different mutations were observed with particular enrichment for NPM1 and FLT3-TKD. Our original hypothesis was that patients with LC would display a distinct mutation profile. Ultimately, the distribution of mutations observed in our cohort of LC patients largely reflects the mutational profile seen in AML patients in general

Alpha-Particle Immunotherapy for Acute Myeloid Leukemia (AML) with Bismuth-213 (213Bi) and Actinium-225 (225Ac)

Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody’s potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the α-emitter 213Bi was conjugated to lintuzumab. The safety, feasibility, and antileukemic activity of 213Bi-lintuzumab was demonstrated in a phase I trial (Jurcic, Blood 2002). Furthermore, 213Bi-lintuzumab produced remissions in 24% of AML patients receiving doses ≥ 37 MBq/kg after partial cytoreduction with cytarabine (Rosenblat, Clin Cancer Res 2010). The widespread use of 213Bi, however, is limited by its 46-min half-life. 225Ac (t½=10 d), a radiometal that generates four α-particles, can be conjugated to antibodies using DOTA-SCN. 225Ac-labeled immunoconjugates can kill in vitro at doses at least 1,000 times lower than 213Bi analogs and prolong survival in mouse xenograft models of several cancers (McDevitt, Science 2001). We sought to determine the safety, pharmacology, and biological activity of 225Ac-linutuzumab in patients with AML.JRC.E.5-Nuclear chemistr