Contributions
Abstract: PB1768
Type: Publication Only
Background
CD19 is broadly expressed across B-cell malignancies, including chronic lymphocytic leukemia (CLL). MOR208 is an Fc-enhanced CD19 antibody mediating potent antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and direct cytotoxicity. Single agent MOR208 has shown promising activity in clinical studies.
Aims
We investigated the in vitro cytotoxicity of MOR208 when combined with the tyrosine kinase inhibitors (TKIs), ibrutinib and idelalisib, and the BCL-2 inhibitor, venetoclax.
Methods
The CLL cell line MEC-1 was treated with 0.3–10 µM ibrutinib, idelalisib or DMSO (control) for 7 days or 3–10 µM venetoclax or DMSO for 24 hours. Inhibition of proliferation, cytotoxicity and impact on CD19 expression were then assessed. ADCC assays with MOR208 incorporated a fixed number of primary human natural killer cells from healthy volunteers as effector cells. By contrast, the number of target cells was reduced according to antiproliferative or cytotoxic effects of the TKIs or venetoclax. Dose-dependent ADCC activity of MOR208 was analyzed by flow cytometry. Cytotoxic effects were studied in at least three independent experiments.
Results
Ibrutinib and idelalisib induced only moderate direct cytotoxicity on MEC-1 target cells but had strong antiproliferative effects. In contrast, venetoclax induced strong cytotoxicity on MEC-1 target cells within 24 hours. Both effects led to reduced tumor target cell numbers in the subsequent ADCC assays. CD19 expression was largely unaffected by all three drugs. The addition of MOR208 to ibrutinib, idelalisib or venetoclax treated target cells resulted in enhanced maximum ADCC when compared with single agent MOR208. EC50 values remained unaltered in TKI or venetoclax treated conditions compared with the DMSO control. Calculations according to Chou-Talalay yielded combination indices below 1 for all three drugs, thus confirming synergistic activity.
Conclusion
The cytotoxic effect of MOR208 was synergistically enhanced when combined with ibrutinib, idelalisib or venetoclax in vitro. These promising data provide a strong rationale for combination of MOR208 with these agents in future clinical trials.
Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology
Keyword(s): CD19, B cell chronic lymphocytic leukemia, antibody
Abstract: PB1768
Type: Publication Only
Background
CD19 is broadly expressed across B-cell malignancies, including chronic lymphocytic leukemia (CLL). MOR208 is an Fc-enhanced CD19 antibody mediating potent antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and direct cytotoxicity. Single agent MOR208 has shown promising activity in clinical studies.
Aims
We investigated the in vitro cytotoxicity of MOR208 when combined with the tyrosine kinase inhibitors (TKIs), ibrutinib and idelalisib, and the BCL-2 inhibitor, venetoclax.
Methods
The CLL cell line MEC-1 was treated with 0.3–10 µM ibrutinib, idelalisib or DMSO (control) for 7 days or 3–10 µM venetoclax or DMSO for 24 hours. Inhibition of proliferation, cytotoxicity and impact on CD19 expression were then assessed. ADCC assays with MOR208 incorporated a fixed number of primary human natural killer cells from healthy volunteers as effector cells. By contrast, the number of target cells was reduced according to antiproliferative or cytotoxic effects of the TKIs or venetoclax. Dose-dependent ADCC activity of MOR208 was analyzed by flow cytometry. Cytotoxic effects were studied in at least three independent experiments.
Results
Ibrutinib and idelalisib induced only moderate direct cytotoxicity on MEC-1 target cells but had strong antiproliferative effects. In contrast, venetoclax induced strong cytotoxicity on MEC-1 target cells within 24 hours. Both effects led to reduced tumor target cell numbers in the subsequent ADCC assays. CD19 expression was largely unaffected by all three drugs. The addition of MOR208 to ibrutinib, idelalisib or venetoclax treated target cells resulted in enhanced maximum ADCC when compared with single agent MOR208. EC50 values remained unaltered in TKI or venetoclax treated conditions compared with the DMSO control. Calculations according to Chou-Talalay yielded combination indices below 1 for all three drugs, thus confirming synergistic activity.
Conclusion
The cytotoxic effect of MOR208 was synergistically enhanced when combined with ibrutinib, idelalisib or venetoclax in vitro. These promising data provide a strong rationale for combination of MOR208 with these agents in future clinical trials.
Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology
Keyword(s): CD19, B cell chronic lymphocytic leukemia, antibody