Reversing resistance

OSLO, Norway—Non-Hodgkin’s lymphoma (NHL) is an indication with substantial unmet medical need, with a growing market forecast to be worth nearly $29 billion by 2026. Preclinical studies investigating the effect of Betalutin (177Lu-lilotomab satetraxetan) on NHL cell lines appear to demonstrate that the drug, as part of a combination regimen, could provide effective therapy for NHL. Nordic Nanovector is attempting to commercialize Betalutin in core markets.

Nordic Nanovector, which presented a poster at the 61^st American Society of Hematology (ASH) Annual Meeting & Exposition in December 2019 in Orlando, has been conducting a research program to investigate resistance mechanisms that enable NHL cells to survive Betalutin treatment and to identify molecules that, when used in combination with Betalutin, could overcome that resistance. The outcome of this research could have an impact on future programs designed to expand the use of Betalutin-based therapies in NHL patients.

According to Nordic Nanovector, a company that develops targeted therapies for hematological cancers, the research presented at ASH built on data presented at the European Hematology Association annual meeting in June 2018. That research demonstrated how a screen of more than 50 different NHL cell lines identified some cell lines that were resistant to Betalutin.

The ASH poster showed how these two aggressive diffuse large B cell lymphoma (DLBCL) cell lines have been used in a new screen where Betalutin has been combined with 384 different anticancer drugs to identify the Betalutin/drug combinations that could potentially contribute to reverting resistance. The CD37 targeting radioimmunoconjugate 177Lu-lilotomab satetraxetan (Betalutin) is currently being evaluated as monotherapy in a clinical Phase 2b trial for patients with follicular lymphoma (FL), in a Phase 1 trial for patients with DLBCL, as well as in a Phase 1b trial in combination with rituximab for patients with relapsed/refractory FL.

Nordic Nanovector investigated the effect of 177Lu-lilotomab satetraxetan in seven activated B-cell like (ABC) DLBCL cell lines. While the radioimmunoconjugate showed anti-tumor activity, primary resistance was observed in a subset of cell lines: U-2932 and RIVA. Both cell lines are representative for TP53 deficient double expressor (DE) DLBCL. Importantly, resistance was not a consequence of reduced binding of the radioimmunoconjugate to cell surface expressed CD37. Armed with this knowledge, Nordic Nanovector set out to identify drugs able to overcome the resistance to 177Lu-lilotomab satetraxetan in both resistant ABC-DLBCL cell lines.

As Jostein Dahle, chief scientific officer of Nordic Nanovector, explained, “Our ongoing research programs and collaborations continue to help us understand how NHL cells react to Betalutin treatment. Understanding the mechanisms of resistance to Betalutin, and how to overcome them, is crucial for being able to deliver optimal treatment to patients with difficult-to-treat tumors. In the case of Betalutin-based treatment, which to date has demonstrated an encouraging clinical profile, such combination strategies could further enhance its potential to become an important option for NHL patients.”

In other news, Nordic Nanovector’s research and development project Nanoyield received a non-dilutive funding of NOK12 million ($1.3 million) from the Norwegian Research Council (Forskningsrådet). The Nanoyield project is targeted at optimizing the production yield of Nordic Nanovector’s CD37-targeting antibody NNV003, the antibody component of the radioimmunoconjugate Alpha37. The project will be conducted in partnership with SINTEF Biotechnology, one of Europe’s largest independent research institutes.

Additionally, Nordic Nanovector received grant funding of €600,000 from Eurostars, a European R&D funding program, to advance the Alpha37 program. Alpha37 comprises NNV003 with the alpha-particle generator lead-212 (212Pb) and is being advanced in an R&D collaboration with Orano Med. Preclinical data presented at international cancer congresses during the past year have indicated that a single injection of Alpha37 is well tolerated and produces a promising anti-cancer effect and subsequent improvement on survival in preclinical models of CD37-positive chronic lymphocytic leukemia (CLL) and NHL.

Dahle summarized, “We are excited to receive this new non-dilutive grant funding from Forskningsrådet to advance the Alpha37 program. Alpha-emitting radionuclides have demonstrated good potential for targeted cancer therapies. Their high energy is limited to a few cell widths, resulting in localized cytotoxicity while sparing surrounding healthy tissues. We have seen very encouraging preclinical evidence demonstrating the potential of Alpha37 to treat CLL and NHL, and with our partners are advancing this exciting candidate towards clinical trials in these indications.”