IMM-101 is thought to act predominantly as a TLR-2/1 agonist
IMM-101 has been shown to be an excellent activator of dendritic cells (DCs) (and several other innate immune cells, such as macrophages and natural killer cells). This activation is thought to be predominantly caused by the binding of certain of IMM-101’s containing Mycobacterium obuense bacterial cell wall components (such bacterial compounds are called in general Microbial Associated Molecular Pattern molecules (MAMPs)) to a specific group of receptors that are expressed on the surface or inside phagocytotic compartments of DCs. A sub-group of these receptors are called Toll-like receptors (TLRs) of which 10 different receptors (TLR1-10) are known in humans.
Based on ongoing research with M. obuense and similar mycobacteria, it is thought that IMM-101 predominantly activates DCs through the binding of MAMPs with TLR-2, with the receptor combination of TLR-2 with TLR-1 (TLR-2/1) being the more dominant one than the combination of TLR-2 with TLR-6 (TLR-2/6); all of which are expressed on the outer cell membrane of DCs. In contrast to certain other mycobacteria used in cancer treatment (e.g. BCG), IMM-101 does not activate TLR-4 (which activation may result in some unwanted immune responses) and there are presently no indications that it activates the other known TLRs (TLR-3, 5, 7, 8, 9 and 10). IMM-101 can therefore be regarded predominantly as a TLR-2/1 agonist.
TLRs form part of a broader group of receptors through which microbes (e.g. bacteria, viruses and fungi) can activate DCs. Together these receptors are called Pattern Recognition Receptors (PRRs). Research is ongoing to find out which other PRRs are activated by IMM-101. The monocyte-inducible C-type lectin (Mincle) receptor is one of those PRRs recently identified to be activated by IMM-101’s characteristic composition of bacterial cell wall components. Besides TLR-2/1, Mincle and potentially additional other undisclosed PRRs are thought to be involved in the binding (and subsequent activation of certain intra-cellular pathways leading to DC activation and cytokine production) of a special selection of specific PRRs without activating the other PRRs. It is hypothesized that this specific blend of activated versus non-activated PRRs drives IMM-101 activated DCs to become optimal inducers of a strong Type I immune response (see More About Immuno-oncology). Other MAMP compositions activate different PRR blends. This is how certain parasites can cause typical Type II immune responses (in which antibodies are predominantly produced) and other bacteria (e.g. probiotic bacteria) can generate regulatory T lymphocytes that suppress overexuberant immune responses.
There are a few TLR-3, 4, 5, 7, 8 and 9 specific agonists under development by other companies, which Immodulon regards as potential competitors, since they also have the potential capacity to activate DCs. These competing products are mostly synthetic single TLR agonists, which generally can only activate one specific PRR instead of IMM-101’s blend of different PRRs, and they lack the physiological normal, spatial distribution and presentation which is the normal, evolutionary imprinted route through which DCs are activated in the body. It is expected that the way in which more natural multiple PRR agonists, like IMM-101, activate DCs – through the simultaneous stimulation of several different activation pathways – leads to a more balanced activation profile than the activation of just one type of receptor, which is unnatural for these DCs and therefore may have the potential to be less effective and/or cause more side effects and safety issues. Only activation through TLR-2/1 or TLR-3 leads to the desired direct generation and activation of cDC1s, which are crucial for anti-tumour immune responses.
IMM-101 activated DCs show a strong increase of CD40, CD80, CD86 and MHC class II expression; these membrane molecules are all essential for proper antigen presentation necessary for strong immune responses1. In addition, IMM-101 activated DCs have increased antigen processing capabilities and produce TNFα and IL-6, which cytokines assist in enhancing immunological responses1. Surprisingly, only part (i.e. IL12-p40) of the IL-12 cytokine is produced following IMM-101’s activation of DCs. The relevance of this is being investigated in our ongoing research activities.
Most importantly, DCs activated by IMM-101 results in a typical strong Type I immune response in the lymph nodes to which these DCs migrate and reside following their contact with and uptake of IMM-101 injected in the skin area that drains on these lymph nodes. Our research has shown that such IMM-101 activated DCs cause the generation of large numbers of IFNγ producing activated CTLs, Th1s, NKs, γδTs and NKTs in these lymph nodes1. These activated immune cells and their released IFNγ are well known to be crucial (together with M1Φs, which are also activated by IMM-101) for an efficient immunological anti-tumour response (see More About Immuno-oncology). DCs activated by IMM-101 can therefore be regarded as activated cDC1s, which others have shown to be essential for optimal activity of the highly popular immune checkpoint inhibitor cancer drugs2 and cancer treatment in general3.
2Salmon, et al. Immunity 2016 44:924-938
3Bötcher JP and Reis e Sousa. Trends in Cancer 2018 4(11): 784-792