Nature Cancer: iNKT cell therapy "recruiter" - dual-specific antibody

Constant Natural Killer T cells (Invariant natural killer T cells, iNKT cells) are congenital CD1d restricted T cells that express constant T-cells (iTCR) and experience a unique differentiation process in the thymus that obtains NK-like properties, including strong cytotoxicity, rapid secretion of cytokines, which can be effectively transported to medium tissue.
unlike NK cells, target recognition of NKT cells is limited by CD1d (the interaction of NKT cells with glycolipids presented by CD1d), similar to T cell recognition targets are limited by HLA.
in some types of tumors, the presence of iNKT cells in primary tumors is associated with good prognosticity.
of studies have shown that iNKT cells have the potential for cancer immunotherapy.
, in a paper published in the journal Nature Cancer, an international team of researchers reported on VHH1D12, a single-stranded dual-specific antibody that stabilizes the interaction of iTCR-CD1d complexes.
that VHH1D12 is effective in stimulating iNKT cells, resulting in a powerful anti-tumor immune response.
The fact that iNKT cell-based therapy has shown safe and promising clinical activity in some cancers has greatly increased the researchers' enthusiasm for cancer treatment by targeting CD1d restrictive iNKT cells.
Figure 1 iNKT Cell-Related Therapy (a) Using CD1d-specific exogenetic (Exog) lipid antigens and derivatives to activate iNKT cell response; b) autologic iNKT cell therapy, i.e. intrabody amplification of the host's iNKT cell population, and re-infusion to patients for treatment, iNKT cells can be modified to make iNKT cells express chime resistance by identifying endogenetic (Endog) ligand-mediated cell killing; Primary subject (CAR) or recombinant TCR (rTCR) to gain the ability to identify tumor-related antigens (TAA); Type that can cause iNKT cell depletion or activation; e) A new dual-functional camel-based single-stranded antibody VHH1D12, which stabilizes iTCR-CD1d interactions and leads to iNKT cell-mediated anti-tumor reactions.
early attempts by Nature Cancer to investigate the cancer potential of iNKT cells in clinical trials took advantage of the highly specific natural glycolipid ligand ligand ligand α-galactosylceramide (α-GalCer) presented to iNKT cells by CD1d (Figure 1a).
This glycolipid-based therapy stimulates type 1 auxiliary iNKT cell response (anti-pathogens, anti-tumor and inflammatory) and type 2 auxiliary iNKT cell response (antibody induction and immunomodulation), thus triggering a wide range of immune responses.
, however, although large doses of α-GalCer intravenously have an immune stimulation effect on iNKT cells, the anti-tumor response induced by such therapies in Phase I clinical trials is minimal.
, the researchers changed their delivery strategy and instead used degeneration cells (DCs) from single-nucleocyte sources to load α-GalCer.
although this change has led to objective mitigation, α-GalCer and its derivatives have a short and very insoluble life in the body, making their preparation challenging.
addition, DC therapy α-GalCer is actually complex, time-consuming, and expensive.
shown in Figure 1b, some iNKT cell-based introphy therapies have also entered Phase I clinical trials and have shown safe and relative clinical efficacy.
same time, iso-iNKT cell therapy is moving towards clinical development (Figure 1c).
other treatments that regulate iNKT cell function are immunomodulation antibodies.
iTCR targeted antibody has been tested in a Phase I clinical trial, as shown in Figure 1d.
In addition, over the past 25 years, scientists have developed a variety of CD1d-specific monoclonal antibodies (mAbs), traditionally considered iNKT cell blockers, because many of these antibodies block the interaction of iNKT cells with CD1d-plus cells.
2 CD1d-specific VHH1D12 activates type I NKT cells (Source: Nature Cancer) In the latest study published in Nature Cancer, Roeland Lameris and others describe the structural basis of an accidentally discovered, unique, iNKT cell-excited bifunct antibody.
the antibody clone (1D12) comes from a collection of CD1d-specific camel-based monochain antibodies (also known as "nanobodies" or "VHHs") that lack monoantimmune Fc fragment chains.
-screened nanoantibodies VHH1D12 show unique excitant activity based on their ability to bind to CD1d and iNKT cell TCR simultaneously in the presence of the corresponding lipid antigen, thereby stabilizing the CD1d-lipid-iTCR ternate complex (Figure 1e).
3 VHH1D12 stabilizes the CD1d-I NKT TCR interaction (Source: Nature Cancer) Studies show that VHH1D12 binds to the outer side of the CD1d cell and interacts with the α chain of iTCR, forming a unique bridge that stabilizes the interaction of CD1d-α-GalCer-iTCR.
this unique feature may be due to the small size of the camel antibody, making it more accessible to the triad's interface.
it is worth noting that iTCR shows an unusually high affinity for CD1d and α-GalCer, so that even moderate levels of α-GalCer and its structural similarities can fully activate iNKT cells.
interestingly, this new study proves that VHH1D12 not only enhances CD1d-α-GalCer-iCTR interactions, but also enhances the low affinity interactions of CD1d endolysaccharine lipids.
this function leads to stronger iNKT cell-mediated anti-tumor immune responses.
VHH1D12 has been shown to enhance iNKT cell-mediated anti-tumor protection without the addition of extra exogenetic high affinity lipids.
Figure 4 VHH1D12 induces the anti-tumor activity of type I NKT cells and improves the survival of animals in the MM model (Source: Nature Cancer) In addition, it should be noted that VH1D12 also exhibits inhibitory activity against other NKT cells that are antagonic to iNKT cell function.
this means that VHH1D12 activates iNKT cells while blocking the activation of other NKT cells, thereby enhancing the specific anti-tumor response triggered by iNKT cells.
, a commentary published by Nature Cancer, notes that, overall, the work of Lameris et al. provides compelling evidence of the therapeutic potential of VHH1D12 and adds a valuable new addition to the iNKT cell-related therapy currently under development.
However, based on current clinical development experience of nanoantibodies and bi-specific monoantibodies (bi-specific mAbs), the life span of dual-functional iNKT cell agonist VHH1D12 may be relatively short compared to traditional monoclonal antibodies, so there is no doubt that the pharmacological properties of such antibodies need to be carefully studied.