In:
Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2235-2235
Abstract:
MEN1112 is a new humanized, defucosylated, monoclonal antibody (mAb) with high specific affinity for Bst1/CD157 antigen. Bst1/CD157 antigen expression on blood cells of acute myeloid leukemia (AML) patients and healthy donors was investigated by flow cytometry using a PE-labeled MEN1112 mAb. Twenty three patients affected with AML have been tested, 18 at diagnosis, 4 at relapse, 1 resistant. In 16 out of 23 patients both bone marrow (BM) and peripheral blood (PB) specimens were evaluated. PB and BM samples from healthy donors (N=2) were also assessed. In healthy donors and AML patients, PB and BM lymphocytes were Bst1/CD157 antigen negative whereas monocytes and neutrophils showed a distinct pattern of MEN1112 mean fluorescence intensity (MIF), with monocytes having the brightest expression. In the stem cell compartment, an intermediate level of MFI was observed (p 〈 0.001). Prevalence of expression of the antigen on patients’ samples was over 90%. On AML blast cells from each single patient, MEN1112 expression was heterogeneous; indeed the antigen was expressed on 50%±29% and 47% ±39% of blasts in BM and PB, respectively. The anti-leukemia activity of MEN1112 on AML cell lines was tested, in vitro, by a flow cytometry-based cell depletion assay in the presence of lymphokine activated immune effector cells: a strong depletion of leukemia cells was demonstrated suggesting that MEN1112 might exert anti-leukemia activity through antibody dependent cell-mediated cytotoxicty (ADCC). The activity of MEN1112 was also tested ex vivo on whole PB showing that the antibody was able to deplete AML blasts in 9 out of 23 patients (47.4 %) with a percentage of AML blast depletion ranging between 4.3 - 66 %. In whole BM from 2 out of 11 evaluable patients MEN1112 induced 68% and 23% of AML blast depletion. Bst1/CD157 shedding assessment showed that, in the sera from AML samples, the concentration of Bst1/CD157 antigen was comparable to that measured in healthy donors. Moreover, since Fcγ receptor (CD16) genotype might be a factor contributing to the antitumor activity of the antibody, the polymorphism CD16-158Phe/Val was analyzed. Five out of 19 samples were homozygous for CD16-158 Phe; 5 were homozygous for CD16- 158 Val and 9 were heterozygous for CD16-158. MEN1112-induced blast depletion was observed for each genotype. Moreover, in an attempt to identify the determinant of MEN1112 activity, % in PB of blast (antigen positive), NK cells or residual normal cells were evaluated. Altogether, these results are promising suggesting the potential for an ADCC-mediated MEN1112 antileukemic effect and they support the clinical development of MEN1112. Disclosures Venditti: Menarini Ricerche SpA: Research Funding. Buccisano:Menarini Ricerche SpA: Research Funding. Del Principe:Menarini Ricerche SpA: Research Funding. Coppola:Menarini Ricerche SpA: Research Funding. Palomba:Menarini Ricerche SpA: Research Funding. Aureli:Menarini Ricerche SpA: Research Funding. Arriga:Menarini Ricerche SpA: Research Funding. Bellarosa:Menarini Spa: Employment. Bressan:Menarini Ricerche SpA: Employment. Manzini:Menarini Ricerche SpA: Employment. Simonelli:Menarini Ricerche SpA: Employment. Binaschi:Menarini Ricerche SpA: Employment. Amadori:Menarini Ricerche SpA: Research Funding. Sconocchia:Menarini Ricerche SpA: Research Funding.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V124.21.2235.2235
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2014
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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