Science

MAIT Engagers

Resolving some of the limitations of classical T-cell engagers to efficiently and directly kill cancer cells and destroy solid tumors.

BIOMUNEX is the leading company worldwide developing MAIT engagers for the treatment of solid tumors.

Using our best-in-class BiXAb® bispecific antibody platform technologies, we have developed MAIT engagers, a new member of the Immune cell engager drug modality. MAIT engagers simultaneously bind a Tumor Associated Antigen (TAA) and the unique, semi-invariant, T-cell receptor (TCR) on MAIT cells (Mucosal Associated Invariant T-cells). MAIT cells are part of the non-conventional cytotoxic T-cell sub-population, that are present throughout the body and are particularly enriched in mucosal and barrier tissues (see below further properties). By bridging a MAIT cell and the tumor cells, the MAIT engager effectively creates an immunological synapse that induces MAIT cell activation, degranulation, proliferation and directed cytotoxicity towards the targeted cancer cells, enabling efficient destruction of solid tumors.

The Biomunex MAIT engager concept was co-invented in collaboration with the “Cancer and Immunity” Unit at the Institut Curie led by Dr. Lantz and Dr. Amigorena.

Identified and described for the first time in 1999 in the Journal of Experimental Medicine², by Dr. Olivier Lantz, Director of the Clinical Immunology Laboratory of the Institut Curie, MAIT cells are abundant in the blood (up to 20% of CD8 population) and are found in all tissues, especially enriched in barrier tissues. Due to their high propensity to migrate into tissue, they are also found in significant numbers in many solid tumors and can directly kill cancer cells.

² Journal of Experimental Medicine – An Invariant T-Cell Receptor α Chain Defines a Novel TAP-independent Major Histocompatibility Complex Class Ib–restricted α/β T-Cell Subpopulation in Mammals (https://doi.org/10.1084/jem.189.12.1907)

Biomunex’s proprietary MAIT-engager program

BMX-500 series

Advantages of BiXAb-MAIT engagers compared to other T cell engagers

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Mode of Action

MAIT engagers are bispecific antibodies that simultaneously bind the unique Va7.2 subunit of the MAIT TCR and a TAA on a cancer cell. All MAIT cells utilize the Va7.2 chain in their TCR and so binding this subunit, confers MA specificity to this cytotoxic T-cell subset (and a very minor fraction of T-cells that could have randomly utilized this alpha chain in their TCR). The MAIT engager bridges the MAIT cell and the cancer cell forming an immunological synapse which results in activation of the MAIT cell and directed cytotoxicity towards the bound cancer cell (see diagram below for more details).

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Efficiency

BiXAb-MAIT engagers are expected to provide a large therapeutic window because, at difference to classical CD3+ T cell engagers, they do not induce cytokine release syndrome and so can be dosed optimally for maximum efficiency. In addition, unlike CD3 engagers, MAIT engagers do not activate the tumor resident regulatory T-cells (Tregs) which can supress the anti-tumor activity of an engager and this is expected to translate to greater efficiency, especially in tumors with high Tregs. Further, MAIT cells can orchestrate an immune response by modulatings several immune cell subsets (including NKs and myeloid cells) which can act in concert to help achieve tumor control. MAIT engager activity in the tumor will elicit a strong “Spark effect” which is summarized in the figure (see below).

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Number

MAIT cells are one of the more abundant populations of cells in the blood and are also naturally tissue resident where they protect against bacteria and viruses. They will also readily traffic into tissues in response to inflammation and are found in significant numbers in most tumors. They are significantly more abundant than the other “unconventional T-cells such as NKT and ɣ/δ T-cells. MAIT cell abundance in tumor and surrounding healthy tissue makes them perfect candidates for new innovative immunotherapies.

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Specificity

Biomunex’s MAIT engagers target the invariant Va7.2 chain of the MAIT TCR which confers specificity to this immune engager approach. Therefore, MAIT engagers do not activate other T-cell subsets such as CD4 or other CD8 T-cells. Specifically, and unlike pan-CD3 T-cell engagers, they do not activate the regulatory T-cell subset, which contributes to an immunosuppressive tumor microenvironment, nor the CD4 T cell population in general that can release IL-6 to kick-start cytokine release syndrome, a severe clinical side effect seen with CD3 T-cell engagers.

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The Spark Effect

The “Spark effect” is termed as such because it renders the idea that MAIT engagers (also CD3 engagers) initiate the primary anti-cancer cytotoxicity activity within the solid tumor: The initial “Spark” of killing.

In the figure, the MAIT engager binds tumor resident MAIT cells and a tumor antigen on the cancer cells which creates an immunological synapse that leads to activation of the MAIT cells and release of cytotoxic granules to directly kill the ligated cancer cell: the “Spark”. The MAIT cells then also proliferate and kill more cancer cells nearby increasing the amount of focused killing: A bigger and more efficient “spark”. The cancer cells die by immunological cell death which releases many cancer neoantigens that are then taken up by dendritic cells and macrophages and presented to the adaptive immune system. There is then a secondary response from the adaptive immune system to these neo-antigens and new, tumor-specific, cytotoxic T-cells attack the cancer, via these tumor neoantigens. The combined impact of the MAIT cells initiating the primary anti-cancer effect and the secondary response from the adaptive immune system should give rise to long term durable responses in patients. In addition, due to their ability to orchestrate the immune system, the activated MAIT cells also contribute further by modulating the dendritic cells and macrophages to increase their antigen presentation activity and activate the NK cells in the tumor microenvironment.

Classical CD3 engagers can struggle to produce an effective “spark” in solid tumors because they also activate tumor resident regulatory T-cells that suppress the cytotoxic T-cells and reduce tumor killing. On the one hand the CD3 engager is activating the CD8 cells to kill the tumor and on the other, is activating the Tregs to dampen down the CD8 activity often resulting in a “poor spark”. In tumors where there is a strong component of Tregs, MAIT engagers are expected to show superior activity.