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E. Gaudio et al.
apoptotic proteins were affected by exposure to MEN1309/OBT076, which induced a downregulation of MCL1 protein and upregulation of BCL2 and BCX-L. The ADC also determined an upregulation of CD20 protein levels. All the changes were maintained when MEN1309/OBT076 was given in combination with the BCL2 inhibitor or the anti-CD20 monoclonal antibody,
and not seen after these two drugs were given as single agents. PARP1 cleavage confirmed apoptosis induction.
Table 2. Anti-tumor activity of MEN1309/OBT076 and IgG-DM4 in B-cell lymphoma cell lines.
GCB-DLBCL
ABC-DLBCL
MCL
MZL
CLL
Median IC50
30 nM
30 nM
15 nM 17.5 nM
IgG-DM4
15-54 nM 15-38.5 nM
The combinations with the PI3K-d inhibitor idelalisib was additive in two cell lines and of no benefit in the other two, while the immunomodulatory agent lenalidomide was additive in one cell line and of no benefit in the remaining three.
A
B
N. of cell lines
15
MEN1309/OBT076 Median IC50 95%CI
200 pM 118 pM-4163 pM
8 10
300 pM 200 pM-3612 pM 100 pM 86-1883 pM
6
2
110 pM 55-465 pM
310 pM n.d.
95%CI
20-38 nM
20-40 nM
34nM n.d.
GCB-DLBCL: germinal center B-cell type diffuse large B-cell lymphoma; ABC-DLBCL: activated B-cell like diffuse large B-cell lymphoma; MCL: mantle cell lymphoma; MZL: mar- ginal zone lymphoma; CLL: chronic lymphocytic leukemia; n.d.: not determined; N: number; CI: confidence interval.
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Figure 2. MEN1309/OBT076 as single agent has in vivo antitumor activity in the activated B-cell like diffuse large B-cell lymphoma OCI- LY10 xenograft model. Treatment with MEN1309/OBT076 and IgG-DM4 started when tumors became visible (100mm3). (A) Control (CTR) group, n=4; IgG-DM4 group, n=4; MEN1309/OBT076 1.25 mg/kg, n=8;
MEN1309/OBT076 2.5 MEN1309/OBT076 5 mg/kg, n=8. In each box-plot, the line in the middle of the box rep- resents the median and the box extends from the 25th to the 75th percentile (IQ: interquar- tile range). Each dot represent a mouse. x- axis: days of treatment. y-axis: tumor volume expressed in mm3. (B) Kaplan-Meier LSS (lymphoma specific survival). MEN1309/OBT076 (5 mg/kg) versus all other groups together. P<0.0001.
mg/kg, n=7;