Description

IPH 2101 (anti-KIR) is a fully human monoclonal antibody blocking interaction between KIR inhibitory receptors on NK (Natural Killer) cells with their ligands. By blocking these receptors, it facilitates activation of NK cells, and, potentially, destruction of tumor cells by the latter. For more details on IPH 2101 mechanism of action and on NK cells, see the section mAbs targeting NK cell. 

First indirect proof of concept in humans

The principle of the mechanism of action of IPH 2101 is based on very convincing validation elements in both animal models and humans in the field of oncology.

The most interesting results are those obtained by Andrea Velardi’s group at the University of Perugia (Ruggeri, et al., 2002) then confirmed and reinforced by other results (Giebel et al., 2003, Leung et al., 2004, Hsu et al., 2005, Kroger et al., 2005) in situations of allogeneic bone marrow grafts (i.e. from donors) in patients with myeloid leukemia or multiple myeloma. They show that the absence of interaction between the KIR and its ligand can translate into a much longer patient survival.

In the situations of allografts, the NK cells of some donors do not have KIR inhibitory receptors compatible with the MHC.I (“self”, their ligand) of the patient (see mAbs targeting NK cell). This leads to an activation of the donor’s NK cells, which can kill the recipient’s tumor cells. These NKs are referred to as alloreactive NKs.
In these situations, it was shown that the presence of alloreactive NKs in humans correlates with the total  absence of relapse even in patients at very advanced stages of the disease, whereas the presence of autologous NKs has no effect.

IPH 2101 aims at mimicking this situation by blocking the NK inhibitory receptors with a pharmacological agent, more easy than the very complex clinical procedure of bone marrow transplantation.
 

Development

Since passing in regulatory pre-clinical development in June 2005 and up until the end of the transfer at the first quarter of 2009, the product has been developed by Novo Nordisk A/S. Since beginning of 2009, Innate Pharma is responsible for the development of IPH 2101 and sponsor of the current clinical studies.

Clinical development

IPH 2101 is today tested in Phase II trials in multiple myeloma (REMYKIR and KIRIMID) and in smoldering myeloma (KIRMONO).
Two Phase I extensions are also ongoing in  acute myeloid leukemia (AML) and in multiple myeloma.

Results for the two Phase I trials have been reported at the 2009 American Society of Hematology (“ASH”) meeting in Décember 2009 (view the press release).

Market potential

Pre-clinical and clinical studies have orientated product development towards onco-hematology indications.

With 13,410 new cases, acute myeloid leukemia represents less than 1% of cancers, but approximately 30% of the new cases of leukemia diagnosed in the United States in 2007. Incidence of multiple myeloma in the United States is 19,900 cases a year. The published scientific data from cellular models show anti-tumor activity by NK cells in several types of cells (melanoma or ovarian cancer notably). The market potential could therefore be very sizeable in case of clinical success.

Furthermore, we were able to demonstrate that the product had a synergistic action in vitro and in mice with certain therapeutic antibodies that have already been approved (rituximab, alemtuzumab). The stimulation of NK cells effectively enhances one of the mechanisms of action of the cytotoxic therapeutic antibodies. This combination approach will be tested early in clinical development and will open up wide prospects for existing and future markets for therapeutic monoclonal antibodies in oncology.

Biobliography

see the section mAbs targeting NK cell.