The benefits of mucosal immunity
Autonomy of the mucosal compartment
A mucosal immune system seems to exist alongside the systemic immune system, developing stimulation and maturation mechanisms independent of the systemic system. (B Cell differentiation in the gut lamina propria, Cerutti et al., Mucosal Immunology, 2008).
The autonomy of the mucosal compartment has been partially demonstrated through the survival of a subpopulation of B Cells, maybe not receptive and very rapidly restored from local memory cells after an anti-CD20+ treatment. It has a specificity towards pathogens and commensal bacteria (Steady state generation of mucosal IgA+ plasmablasts is not abrogated by B cell depletion therapy with rituximab , Henrik et al., Blood 2010).
The mucosal-related antibody: IgA
With 66 mg/kg/day, IgA is the most prolifically produced and the second most circulating isotype after the IgG isotype. Long considered as an anti-inflammatory antibody involved in maintaining the mucosal homeostasic balance, it has recently been demonstrated that IgA is also able to activate or inhibit inflammatory responses. These demonstrations rely particularly on the identification of several IgA receptors expressed in myeloid cells (neutrophils, eosinophils, monocytes and dendritic cells derived from monocytes and many from macrophages).
IgA is a powerful tool with a strong therapeutic potential, which still needs to be fully explored.
IgA: a tool against colorectal cancer
Colorectal cancer is the second most frequent cancer in women (after breast cancer) and the third in men (after lung and prostate cancers). Moreover, survival chances are quite poor with only one in two people diagnosed in remission. The critical reason is the late diagnosis of colorectal cancer.
Currently, only two main immunotherapies are used in support of first-line chemotherapy: one that inhibits tumor growth by neutralizing the EGF receptor expressed on the tumor cell surface. The other targets the formation of blood vessels irrigating the tumor. These treatments are expensive: for example, 8 weeks of treatment with Erbitux, a targeted therapy produced by Merck-Serono, cost 30,000$.
Until now, there is only one immunotherapy molecule which directly targets a cancer cell marker. However, depending on the KRAS genetic status, only half of patients can benefit from this treatment.
B Cell Design is now proposing this kind of approach by targeting the CEA (carcinoembryonic antigen, CEACAM-5) which is over-expressed in more than 80% of colorectal cancers.
CEA is part of a family composed of 12 members, whose functions vary from cell adhesion, to intracellular and extracellular signal cascades, cell migration, inflammation, angiogenesis, etc. In healthy conditions, CEA is secreted naturally by the digestive tube in low concentration, but is over-expressed in more than 80% of colorectal adenocarcinomas. Even if CEA is also over-expressed in several cancers, it is strongly related to the risk of recurrence. Indeed, around 60% of people with high CEA have a clinical recurrence a few months later.
In addition to its targeted therapy application, CEA could be used in immunoscintigraphy to detect primary tumors and metastasis. Several studies are currently in progress.
B Cell Design uses IgA to target CEA.
IgA is the most heavily produced isotype and is able to activate inflammatory pathways through IgA receptors present on myeloid cells.
Currently, all monoclonal antibodies used in targeted therapy are IgG which act on Fcgamma receptors (FcyR). However, several in vitro studies showed that tumor cell elimination was more effective with IgA targeting FcalphaRI (CD89) (Valerius, JI,2014 ; VanEgmond, Current Top Microbiol Immunol, 2014). Moreover, within peritoneal and pulmonary xenograft models, IgA anti-EGFR showed a significant anti-tumoral effect against A431 cells. The same effect has been highlighted for B16F10-EGFR cells within immunocompetent mice with pulmonary metastasis.
Using IgA for targeted therapy offers several benefits:
- Recruitment of another population of effector cells (polynuclear cells are 40 times more numerous than NK cells)
- Treatment resistance due to FcReceptor polymorphism is by-passed by IgA’s engagement with the FcalphaReceptor.
- IgA mucosal tropism is the key advantage in addressing solid mucosal tumors