About this program

Monalizumab (previously IPH2201) is a checkpoint inhibitor, which is focused on re-establishing a broad anti-tumor response mediated by both NK and T cells.

Monalizumab is a first-in-class humanized IgG4 targeting NKG2A receptors expressed on tumor infiltrating cytotoxic NK and CD8 T lymphocytes.

CD94/NKG2A is an inhibitory receptor binding HLA-E. By expressing HLA-E, cancer cells can protect themselves from killing by NKG2A+ immune cells. HLA-E is frequently up-regulated on cancer cells of many solid tumors or hematological malignancies. Monalizumab, a humanized IgG4, blocks the binding of NKG2A to HLA-E allowing activation of NK and cytotoxic T cell responses. In some types of cancers, high levels of HLA-E appear to confer poorer prognosis. Hence, monalizumab may re-establish a broad anti-tumor response mediated by NK and T cells. Monalizumab may also enhance the cytotoxic potential of other therapeutic antibodies.

Monalizumab is currently in Phase II development in various cancer indications and combinations. Innate Pharma and AstraZeneca partner in the development of monalizumab in a co-development and commercialization agreement.

Monalizumab acts on both T cells and NK cells

Monalizumab is the only checkpoint inhibitor developed to date that is capable of acting simultaneously on T and NK cells, which could provide a more effective immune response. It also acts on tumor-infiltrating immune cells, i.e. a targeted action which could translate into a favorable benefit / risk profile.

Mechanism of action of anti-NKG2A

 

The financial terms of the agreement include cash payments of up to $1.275 billion to Innate Pharma as well as double digit royalties on sales. The initial payment is $250 million, which includes a consideration for the exclusive global rights to AstraZeneca to co-develop and commercialize monalizumab in combination with durvalumab (MEDI4736) and access to monalizumab in monotherapy and other combinations in certain areas. AstraZeneca will pay to Innate a further $100 million prior to initiation of Phase III development, as well as additional regulatory and sales-related milestones of up to $925 million. AstraZeneca will book all sales and will pay Innate double-digit royalties on net sales. The arrangement includes the right for Innate to co-promote in Europe for a 50% profit share in the territory.

A broad exploratory clinical program is ongoing, investigating monalizumab in monotherapy and in combination with other agents in various indication.

The development plan includes:

See the full list of ongoing trials with monalizumab on clinicaltrials.gov.

By blocking the inhibitory function of NKG2A receptors on immune cells, monalizumab aims to restore the immune system’s ability to destroy abnormal cells. NKG2A is a receptor for HLA-E, a molecule expressed on the surface of most lymphocytes and on a wide variety of viral, inflammatory and malignant cells. By expressing HLA-E, abnormal cells protect themselves from destruction by the immune cells expressing the NKG2A receptor.

The overexpression of HLA-E in several cancer types suggests that it could act as a major mechanism of tumor escape.

HLA-E is overexpressed in a wide variety of tumors types:

  • Up to 70-90% of patients with cancers of the head and neck, ovary, endometrium, colon, cervix, lung and various types of leukemia and lymphoma;
  • Up to 50% of all cases of melanoma and esophageal cancers.

All these types of cancer are potential indications for monalizumab.

The clinical development plan is therefore based on HLA-E expression to determine which cancers could respond best to treatment by monalizumab.

Head and Neck, squamous cell carcinoma

Colon carcinoma

Breast carcinoma

Documents: 

AttachmentSize
SITC 2018: Monalizumab in combination with cetuximab in R/M SCCHN: Clinical results and preliminary biomarker analyses1.41 MB
ESMO 2018: Phase II study of monalizumab in combination with cetuximab in R/M SCCHN1.23 MB
ESMO 2018: Changes in the innate immune system as early events in cancer2.24 MB
ECI 2018: Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells2.32 MB
ASCO 2018: First-in-Human dose escalation of monalizumab plus durvalumab with expansion in patients with MSS colorectal cancer175.32 KB
AACR 2018: Phase II of monalizumab with cetuximab in previously treated R/M SCCHN: preliminary assessment of safety and efficacy1.37 MB
AACR 2018: NKG2A immune checkpoint blockade potentiates cetuximab induced ADCC in head and neck cancer preclinical model1.13 MB
AACR 2018: Combination of monalizumab and durvalumab as a potent immunotherapy treatment for human solid cancers350.81 KB
ITOC5 2018: Next generation immunotherapies: NK cells and other targets1.95 MB
CRI-CIMT-EATI-AACR ICI 2017: Combined blockade of PD-L1 and NKG2A enhances anti-tumor CD8+ T cell response1.16 MB
AACR 2017: Safety of monalizumab in combination with cetuximab: a Phase Ib/II study in R/M SCCHN339.78 KB
AACR 2017: NKG2A checkpoint receptor expression on tumor-infiltrating CD8+ T cells restrains efficacy of immunotherapy 1.51 MB
ENA 2016: Dose ranging study of monalizumab in patients with gynecologic malignancies: A trial of the CCTG911.89 KB
SITC 2016: NK, T cells and IFN-gamma are required for the anti-tumor efficacy of combination-treatment with NKG2A & PD1/PDL1 IC720.01 KB
AACR 2016: NKG2A immune checkpoint blockade enhances the anti-tumor efficacy of PD-1/PD-L1 inhibitors in a preclinical model239.61 KB
Presentation at the 13th TAT Congress: rationale and protocol of the Phase I/II trial of IPH2201 in ovarian cancer1.66 MB