New drug active across subtypes of DLBCL

Allison Berger, PhD

Barcelona—An investigational drug exhibits antitumor activity across multiple subtypes of diffuse large B-cell lymphoma (DLBCL) and is more active than bortezomib, according to a preclinical study.

Past research indicated the second-generation proteasome inhibitor MLN9708 is effective against lymphoma. So researchers at Millennium Pharmaceuticals, Inc., the company that manufactures MLN9708, attempted to determine the drug’s efficacy in DLBCL.

“[MLN9708 is] a dipeptidyl leucine boronic acid with similar in vitro properties and similar scaffold as bortezomib,” said Allison Berger, PhD, a researcher at Millennium. “However, it shows improved antitumor activity in preclinical models of lymphoma and solid tumors compared to bortezomib.”
 
So Dr Berger and her colleagues tested MLN9708 in activated B-cell-like (ABC) DLBCL, germinal center B-cell-like (GCB) DLBCL, and a model distinct from ABC- and GCB-DLBCL. She presented the results at the 15th Congress of the European Hematology Association, which took place June 10-13.

The researchers began by implanting immunocompromised mice with subcutaneous xenografts of OCI-LY10 (ABC-DLBCL), PHTX-22L (ABC-DLBCL), and WSU-DLCL2 (non-ABC-/non-GCB-DLBCL). They also took luciferase-tagged OCI-LY7 (GCB-DLBCL) cells and injected them into immunocompromised mice.

MLN9708 hydrolyzes to its biologically active form, MLN2238, upon exposure to aqueous solutions or plasma. So mice with each type of DLBCL were exposed to MLN2238 at varying doses for 3 weeks. As a comparison, other DLBCL-infected mice were given bortezomib at varying doses.

“The major difference that we know of between MLN2238 and bortezomib, at the biochemical level, is a difference in proteasome dissociation half-life,” Dr Berger said. “We see that MLN2238 has a shorter proteasome dissociation half-life, at 18 minutes compared to bortezomib at 110 minutes, and we believe this difference in half-life gave way to difference in biodistribution, which we evaluated in xenograft models of DLBCL….”

The team found that MLN2238 was active across all tested subtypes of DLBCL, and its activity surpassed that of bortezomib.

In the OCI-LY10 xenograft model of ABC-DLBCL, the maximum tolerated dose (MTD) of MLN2238 was 18 mg/kg once weekly; mice given this dose experienced tumor growth inhibition (TGI) of 88%. TGI was 66% when MLN2238 was administered at 8 mg/kg once weekly and 49% when the drug was given at 4 mg/kg once weekly. The MTD of bortezomib, 0.8 mg/kg twice weekly, resulted in the lowest TGI, at 42%.

In the PHTX-22L model of ABC-DLBCL, MLN2238 given at 11 mg/kg twice weekly elicited TGI of 96%. TGI measured 92% when MLN2238 was given at 7 mg/kg twice weekly, 85% at 11 mg/kg once weekly, and 37% at 3.5 mg/kg twice weekly. The MTD of bortezomib elicited substantially lower TGI, at 12%.

MLN2238 also reduced tumor burden in the OCI-LY7 model of GCB-DLBCL. TGI measured 80% when MLN2238 was given at 4 mg/kg once a day. TGI was considerably lower with bortezomib; it was 24% when the drug was administered at 1.0 mg/kg once weekly and 15% when the drug was given at 0.4 mg/kg once daily. 

In the WSU-DLCL2 model of non-ABC-/non-GCB-DLBCL, MLN2238 proved more active than bortezomib once again. MLN2238 given intravenously at 14 mg/kg twice weekly elicited TGI of 56%, as compared to 10% TGI observed with 0.8 mg/kg of bortezomib given intravenously twice weekly.

Results were similar when both drugs were administered subcutaneously in the WSU-DLCL2 model. A daily dose of MLN2238 at 4 mg/kg resulted in TGI of 71%, as compared to 22% TGI with bortezomib given at 0.4 mg/kg daily.

Dr Berger said the favorable results observed with MLN9708 underline the need for further study of the drug. It is currently being evaluated in four phase 1 trials—one in relapsed/refractory lymphoma, two in multiple myeloma, and one in nonhematologic malignancies.