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CD205 targeting in lymphomas
naked antibody recognizing the same epitope targeted by MEN1309/OBT076. No direct anti-tumor effect is report- ed for the naked antibody MEN1309/OBT076.7 It is note- worthy that the expression level of CD205 in cell lines measured at the level of mRNA, total protein or cell sur- face protein correlated with the sensitivity to MEN1309/OBT076. Furthermore, a clinical DLBCL speci- men-derived CD205 signature also correlated with the in vitro response to the drug. In contrast, the expression of two annotated CD205-CD302 intergenically spliced tran- scripts5 did not affect the anti-tumor activity of MEN1309/OBT076.
Finally, MEN1309/OBT076 was beneficially combined with other targeted agents, especially the BCL2 inhibitor venetoclax and the anti-CD20 monoclonal antibody ritux- imab. The latter combination, that had shown the best in vitro results, was successfully validated in vivo using a xenograft model.17 Interesting clinical data are also already available for combinations with other ADC.18,19 The mech- anisms leading to better anti-tumor activity can differ. The concomitant exposure of lymphoma cells to rituximab and to the anti-CD37 ADC IMGN529/Debio1562 leads to
improved anti-lymphoma activity due to an increased internalization of the latter.20 The benefit of combining the anti-CD22 inotuzumab ozogamicin (CMC-544) with rit- uximab could be due to both an early upregulation of CD20 with increased direct cytotoxicity of the anti- CD2021 or to the addition of the direct (inotuzumab ozogamicin), complement and/or cellular dependent (rit- uximab) mechanisms of actions of the compounds.22 Here, we observed that exposure to MEN1309/OBT076 was fol- lowed by upregulation of the rituximab target CD20 and downregulation of the anti-apoptotic protein MCL1, known to counteract the activity of venetoclax in DLBCL cells,23 two changes that could support the observed syner- gisms. Moreover, the addition of venetoclax also counter- acts the BCL2 upregulation seen after the ADC.
In conclusion, the first-in-class ADC targeting CD205, MEN1309/OBT076, demonstrated strong pre-clinical anti- tumor activity in lymphoma. Our data sustain the ongoing clinical CD205-Shuttle study (clinicaltrials.gov identifier: NCT03403725) of MEN1309/OBT076 as single agent, and provide the rationale for further investigations also in combination therapy.
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