For the second time this month Nordic Nanovector, a biotech company focusing on the development and commercialisation of novel targeted therapeutics in hematology and oncology, announced a major agreement for the development of novel antibody-drug conjugates. In early October, the company announced an agreement for the development of novel CD37-targeting antibody-drug conjugates for the treatment of leukemias with South Korea-based LegoChem Biosciences.
Leukemias are orphan diseases with a significant unmet medical need, applicable indications representing a growing market worth over U.S. $ 5 billion by 2020.
“This strategic project extends our ADC portfolio in hematological cancers… and … will speed up the development processes while reducing the development costs of an ADC.”
“This project extends our portfolio of ADCs to further hematological cancers. Nordic Nanovector has an established chemistry, manufacturing, and controls (CMC) process for their antibody which will speed up processes and reduce the development costs of an ADC.”
This collaboration is part of Nordic Nanovector’s strategy to develop its pipeline of targeted therapies to include antibody products conjugated to anti-cancer compounds that are not radionuclides.
“We are pleased to further expand our R&D activities into the ADC area with Heidelberg Pharma in this second strategic collaboration, following closely the collaboration announced recently with LegoChem,” said Jostein Dahle, Nordic Nanovector’s Chief Scientific Officer.
“During the past year, we have made important steps to execute our strategy designed to build a pipeline of innovative antibody-radionuclide conjugates or ARCs and ADCs that combine our expertise and platform with complementary technologies from expert partners. This strategy is aimed at creating multiple new targeted treatment options for patients who suffer a range of leukaemias and lymphomas,” Dahle added.
Nordic Nanovector’s lead clinical-stage product is Betalutin® (177Lu-lilotomab satetraxetan) is a novel antibody radionuclide conjugate currently tested in a phase I/IIa first-in-human dosage escalation trial for patients with relapsed CD37+ indolent non-Hodgkin’s lymphoma. It is the first in a new class of ARCs designed to improve upon and complement current options for the treatment of non-Hodgkin Lymphoma (NHL).
Antibody-radionuclide Conjugates are the backbone of radioimmunotherapy or RIT. It is a molecular targeted radionuclide therapy whereby low dose rate-irradiation from radionuclides is delivered to tumor cells using mAbs directed to tumor antigens. The cytotoxic mechanisms involve both radiobiological and immunological processes. RIT delivers a heterogeneous low-dose-rate irradiation to the targeted tumor. 
Betalutin, which targets CD37, comprises the tumor-seeking anti-CD37 murine antibody lilotomab (previously known as HH1; developed by Norwegian Radium Hospital/Radiumhospitalet), is conjugated to lutetium-177 or 177Lu, a low intensity radionuclide (a beta emitter with a range of approximately 0.5 millimeters / i.e. ~ 50-cell radius) which causes tumor cell death through irreversible double-stranded DNA breaks.
The drug is rapidly internalized when bound to CD37 thereby anchoring 177Lu inside the cell, enabling a prolonged irradiation of tumor cells within the ~50-cell radius. This localized multi-cell kill mechanism of action (the ‘crossfire effect’) destroys malignant cells that do not express CD37 or that have limited blood supply within a tumour mass, and thereby offers a significant advantage over single-cell kill effected by immunotherapy and chemotherapy.
Preliminary data has shown promising efficacy and safety profile in an ongoing Phase I/II study in a difficult-to-treat NHL patient population.
Ideal therapeutic agent
CD37 is a different antigen compared to other drugs targets for NHL. It is expressed by adult B-cells and is present on the majority of B-cell lymphoma cells. As a result, it is an ideal therapeutic target for CD37-based ARC therapies in relapsed lymphoma patients that do not respond to the standard CD20-based therapy with rituximab (Rituxan®; Genentech/Roche), providing greater anticipated activity and a potential synergistic effect.
Today, only two antibody-radionuclide conjugates targeting the CD20 antigen have been approved. This includes the intact murine immunoglobulins 131I-tositumomab, (Bexxar®; GlaxoSmithKline) and 90Y-ibritumomab tiuxetan, (Zevalin®, Spectrum Pharmaceuticals). 131I-tositumomab is now discontinued.
Radionuclides such as 177Lu with shorter-range energy emissions should be more favorable in the setting of MRD. Moreover, 177Lu presents better physical properties than 131I-tositumomab, improving the safety of antibody-radionuclide conjugates-based radioimmunotherapy .
The first regulatory submission of Betalutin is anticipated in 2019.
“This project extends our portfolio of ADCs to further haematological cancers. Nordic Nanovector has an established chemistry, manufacturing, and controls (CMC) process for their antibody which will speed up processes and reduce the development costs of an ADC,” Professor Dr Andreas Pahl, Head of Research & Development and member of the Management Board of Wilex and Heidelberg Pharma, commented.
Heidelberg Pharma is focused on developing an innovative ADC technology platform based on the compound Amanitin, a potent, bicyclic octapeptide RNA-polymerase II inhibitor isolated from the Green Deathcap mushroom Amanita phalloides. The compound interferes with the eukaryotic transcription process at very low intracellular concentrations, making it an ideal drug for the use with antibodies binding at low-copy number antigens.
Amanitin-based ADCs has shown outstanding activity in therapy-resistant tumor cells (e.g. cells expressing multi-drug resistant transporters, tumor-initiating cells and non-dividing cells) at pico molar concentrations. One of the unique aspects of amanitin is that it has a water-soluble structure, resulting in antibody-drug conjugates with low tendency for aggregation, even using higher drug to antibody ratios (DAR).
Heidelberg Pharma’s lead candidate HDP-101, a BCMA ATAC, has been selected for the preclinical and clinical development in multiple myeloma, the third most common hematologic cancer.
In August 2015 Roche announced that it discontinued its partnership with the Wilex subsidiary Heidelberg Pharma for the development of antibody-targeted amanitin conjugates.