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 co-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.

Monalizumab is currently in Phase I and Phase I/II clinical trials in various tumor indications and combinations. The initial development plan includes: Phase II combination clinical trials with durvalumab (MEDI4736), an anti-PD-L1 immune checkpoint inhibitor developed by MedImmune/AstraZeneca, in solid tumors; multiple Phase II trials planned by Innate Pharma to study monalizumab both as monotherapy and in combination with currently approved treatments across a range of cancers; and the development of associated biomarkers.

In a single- and multiple-dose Phase I dose-escalation safety trial in patients with rheumatoid arthritis, monalizumab appeared to have a safe and well-tolerated profile at all doses tested.

 

Setting

Indication

status

Monotherapy

Phase I/II

Gynecological cancers

Up to 98 patients

Started September 2015

Preliminary safety data at EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium 2016

Combination ibrutinib

Phase I/II with dose escalation and cohort expansion

Chronic Lymphocytic Leukemia | Relapsed or refractory

Up to 45 patients

Started October 2015

Combination cetuximab

Phase I/II with dose escalation and cohort expansion

Head & Neck cancer | Relapsed or refractory

Up to 70 patients

Started December 2015

Combination durvalumab (anti-PD-L1)

Phase I with dose escalation and cohort expansion

Advanced solid tumors

Up to 208 patients

Started February 2016

(AstraZeneca)

Monotherapy

Phase I

Hematological malignancies

Up to 18 patients

Started October 2016

 

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