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Mantle cell lymphoma

CHICAGO—The radioimmunoconjugate 177Lu-NNV003 has demonstrated activity against non-Hodgkin lymphomas (NHLs).

Experiments showed that 177Lu-NNV003 can inhibit proliferation in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL) cell lines.

177Lu-NNV003 also exhibited an antitumor effect and prolonged survival in mouse models of MCL, DLBCL, and CLL.

These results were presented at the AACR Annual Meeting 2018 (abstract 848).

This research was conducted by employees of Nordic Nanovector and other researchers. Nordic Nanovector is the company developing 177Lu-NNV003.

177Lu-NNV003 consists of a chimeric antibody targeting CD37 (NNV003) conjugated with p-SCN-Bn-DOTA, which chelates the β-emitting radionuclide lutetium-177.

The researchers found that 177Lu-NNV003 inhibited proliferation in all 3 NHL cell lines tested—MEC-2 (CLL), DOHH2 (DLBCL), and REC-1 (MCL). DOHH2 was the most radiosensitive cell line.

The unlabeled NNV003 antibody, on the other hand, did not exhibit an antiproliferative effect in these cell lines. However, NNV003 did induce antibody-dependent cellular cytotoxicity in MEC-2 and DOHH2 cells and antibody-dependent cellular phagocytosis in MEC-2 cells.

The researchers found that 177Lu-NNV003 targeted CD37-positive cells and demonstrated antitumor effects in mouse models of MCL, CLL, and DLBCL.

REC-1 model

177Lu-NNV003 prolonged survival in CB17 SCID mice injected with REC-1 cells and cured 50% to 60% of the mice.

Median survival times were 55 days in mice that received sodium chloride (NaCl), 85 days in mice that received NNV003 (0.167 mg/kg), and 61 days in mice that received 177Lu-IgG1 (100 MBq/kg).

On the other hand, mice treated with 177Lu-NNV003 had a median survival of 152 days (100 MBq/kg), or the median survival was not reached (50 MBq/kg).

The difference in survival was significant for 177Lu-NNV003 recipients compared to recipients of NaCl (P<0.001) or 177Lu-IgG1 (P<0.002).

MEC-2 model

177Lu-NNV003 also prolonged survival in NRG mice injected with MEC-2 cells.

The median survival was 21 days in mice that received NaCl, NNV003 (2 x 0.33 mg/kg), or 177Lu-IgG1 (200 MBq/kg).

However, mice treated with 177Lu-NNV003 had a median survival of 32 days (200 MBq/kg) or 29 days (2 x 200 MBq/kg).

The difference in survival was significant for 177Lu-NNV003 recipients compared to recipients of 177Lu-IgG1 (P<0.025) or 2 x NNV003 (P<0.02).

DOHH2 model

RAG-2 mice injected with DOHH2 cells had survival times surpassing 200 days after treatment with NNV003 or 177Lu-NNV003.

The median survival was not reached in mice that received NNV003 (at 2 or 30 mg/kg) or 177Lu-NNV003 (at 200, 300, or 400 MBq/kg). But the median survival was 46 days in mice that received NaCl and 47 days in mice that received 177Lu-IgG1 (300 MBq/kg).

The difference in survival was significant for recipients of NNV003 or 177Lu-NNV003 compared to recipients of 177Lu-IgG1 or NaCl (P<0.001 for all).

Toxicity and biodistribution

The researchers noted that the 177Lu-labeled antibodies caused transient hematologic toxicity in the mice.

In the MEC-2 and DOHH2 models, there was no redistribution of 177Lu-NNV003 in organs after initial uptake. (The researchers did not report on biodistribution in the REC-1 model.)

177Lu-NNV003 had low uptake in the liver, spleen, kidneys, and femur. The researchers said this suggests 177Lu-NNV003 is stable in vivo, as free lutetium-177 tends to accumulate in bones.


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