Abstract
1011
Introduction: The C-X-C chemokine receptor type 4 (CXCR4) is heavily expressed in many types of cancers and contributes to tumor growth, survival, and metastasis. We report the results of a novel CXCR4-targeting radiotherapeutic agent, [177Lu]Lu-BL01, on mice bearing Burkitt lymphoma xenografts.
Methods: The linear amino acid sequence of BL01 was synthesized using solid-phase peptide synthesis based on the sequence of LY2510924 (IC50 = 0.079 nM) with an additional Lys at the C-terminus. The linear peptide sequence was cyclized on-resin and DOTA(OtBu)3-OH was coupled to the Lys side chain, followed by deprotection and cleavage from the resin. The cold standard and [177Lu]Lu-BL01 were prepared by incubating BL01 with non-radioactive LuCl3 and [177Lu]Lu-BL01 in acetate buffer, respectively, followed by HPLC purification. Endoradiotherapy studies were performed on mice bearing DAUDI Burkitt lymphoma xenografts with dose groups of 2.22 MBq, 6.29 MBq, 12.95 MBq and 25.03 MBq, and vehicle control (n=6). Mice were monitored and tumor sizes measured either daily or every other day. Mice were euthanized when they reached humane endpoints. Statistical analyses were performed with GraphPad. Results: BL01 was synthesized with a 9% yield and Lu-BL01 was synthesized with a yield of 79%. [177Lu]Lu-BL01 was synthesized with a decay-corrected radiochemical yield of 65 ± 8% (n=2) with a >99% radiochemical purity. Endoradiotherapy studies showed decreased tumor volume and growth between the vehicle control and treated groups. Dose groups of 2.22 MBq and 6.29 MBq demonstrated only tumor size reduction, whereas groups of 12.95 MBq and 25.03 MBq demonstrated complete tumor regression followed by regrowth. Mice in the 12.95 MBq and 25.03 MBq groups had tumor regrowth after an average of 5 and >24 days of tumor regression, respectively. Using an ANOVA 2-way statistical analysis, a statistically significant difference was observed between tumor sizes in the vehicle group versus the 2.22 MBq (p<0.001 at day 6 and later), 6.29 MBq (p<0.001 at day 6 and later), 12.95 MBq and 25.03 MBq groups (p<0.05 at day 4 and p<0.0001 at day 6 and later). The 2.22, 6.29, 12.95, and 25.03 MBq groups experienced an increase in overall median survival by 2.5, 6, 10.5, and >6.5 days, respectively. Conclusion: [177Lu]Lu-BL01, a new CXCR4 targeting peptide, demonstrates radiotherapeutic efficacy in a mouse model of non-Hodgkin B-cell lymphoma.