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E. Gaudio et al.
Figure 4. Combined MEN1309/OBT076 and rituximab shown higher in vivo anti-tumor activity than the single agents in the activated B-cell like diffuse large B-cell lymphoma OCI-LY10 xenograft model. Treatment with MEN1309/OBT076 (2.5 mg/kg), rituximab (5 mg/kg), their combination or vehicle started when tumors became visible (>100 mm3). In each box-plot, the line in the middle of the box represents the median and the box extends from the 25th to the 75th percentile. CTR: control; IQ: interquartile range. y-axis: tumor volume in mm3; x-axis: days of treatment.
is not shared by other antibody or cell1,14-16 based therapies, make MEN1309/OBT076 a very interesting novel com- pound for lymphoma patients.
We did not observe toxicity in our in vivo models, in agreement with reports from in vivo studies of solid tumor models,7 but MBH1309/OBT076 does not significantly cross-react to the mouse CD205.7 Toxicity studies per- formed on cynomolgus monkeys, whose CD205 cross- reacts to MBH1309/OBT076, have shown moderate toxi- city with neutropenia as main adverse event.7 There is no difference in CD205 expression pattern between humans and cynomolgus monkeys across 33 different normal tis- sues, with a membranous/cytoplasmic staining of mononuclear cells in several tissues, including lymph nodes and spleen.7 Here, we exposed human PBMC from two healthy donors to the MEN1309; no cytotoxicity was observed despite the fact that the B cells expressed CD205 levels similar to those observed in a sensitive DLBCL cell line. One reason could be that circulating B cells are not proliferating and are thus less sensitive to the payload. This would agree with the suggested explanation of the low toxicity observed in CD205 positive normal tissues in cynomolgus monkeys.7
The anti-tumor activity of MEN1309/OBT076 appeared to be mediated by the ADC binding to its target as shown by the very high correlation between IC50 values and tar- get expression, and by competition experiments with a
Table 3. In vitro assessment of MEN1309/OBT076 combinations with targeted agents.
Cell line
HBL1
Drug 2
Idelalisib
Median combination index
0.96^
2.51
1.14 0.91^ 1.31 1.46 0.94^ 1.47 0.57* 0.8* 0.27* 0.47* 0.51* 0.86* 1.04^ 0.49*
95% CI
0.78-1
1.91-2.76
1.02-1.32
0.7-1.4
0.92-2.34
1.19-1.58
0.64-1.44
0.97-2.08
0.51-0.67
0.42-2.37
0.22-0.33
0.39-0.8
0.32-0.7
0.68-0.53
0.75-1.52
0.32-0.83
OCI-LY-10
TMD8
U2932
HBL1
OCI-LY-10
TMD8
U2932 Lenalidomide
Idelalisib Idelalisib Idelalisib Lenalidomide Lenalidomide Lenalidomide
HBL1 OCI-LY-10 TMD8 U2932 HBL1 OCI-LY-10 TMD8 U2932
Rituximab Rituximab Rituximab Rituximab Venetoclax Venetoclax Venetoclax Venetoclax
Cell lines were exposed to increasing concentrations of MEN1309/OBT076 and/or of the other compound (drug 2) for 72 hours. Based on the Chou-Talalay Combination Index, the effect of the combinations was defined as beneficial if synergistic (<0.9) or additive (0-9-1.1). CI: confidence interval.
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