Image by Ed Uthman
Burkitt lymphoma
An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.
PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.
Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.
Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.
These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.
“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.
“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”
With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.
The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.
Results in NHL
The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.
PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.
PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.
Results in MM
The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.
Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.
On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).
PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).
The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).
The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).
Results in AML
The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.
They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).
PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).
PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.
The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.
The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.
Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.
“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”
PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.
