The mucosal immune system is responsible for surveillance
of infectious agents and triggering antibody responses to
these agents. In the gut, this mechanism is dependent on an
active sampling of intestinal contents by specialized cells,
called M cells, which transport antigens and microparticles
to the underlying immune tissue. This transport, called transcytosis,
relies on specific receptors able to selectively bind antigens
and microorganisms posing the greatest threat. Using TOGA®,
Neurome has identified these epithelial cell transcytosis
receptors. Such receptors are ideal targets for vaccine delivery
systems, and Neurome is developing a new technology that takes
advantage of these specialized receptors for targeted, receptor-mediated
delivery of specialized synthetic vaccines to mucosal sites
such as the nasal epithelium and small intestine.
The current understanding of mucosal immune surveillance points
to a critical role for M cells in the active transcytosis
of antigens and particles from the intestinal lumen to the
underlying lymphoid tissue.
Until now, the difficulties in isolating M cells have limited
the scientific understanding of their function, and the array
of receptors responsible for transcytosis. To identify the
critical genes involved in M cell function, we used Neurome’s
highly sensitive and quantitative technology, TOGA®, to
identify those genes specifically expressed in induced M cells.
TOGA® permits the accurate identification of genes with
regulated expression among extremely small cell or tissue
samples, and when applied to samples of human intestinal epithelium
cell lines and microdissected animal tissues, yielded several
candidate target receptors.
Fluorescence images of intestinal Peyer's Patch, stained with a fluorescent lectin specific for M cells (red) and with fluorescent in situ hybridization probe specific for an M cell specific gene transcript (green). The overlaid image shows co-localization of the lectin binding and gene expression in the same cells.
These receptor genes were cloned,
and their sequences were used to confirm expression in specific
tissues and cells (such as M cells) of the mucosal immune
system of mice, monkeys, and humans. The genes were also expressed
in cell lines, which were then used for experimental selection
of synthetic short peptide ligands specific to each candidate
Neurome is developing an entirely new vaccine delivery technology,
using a set of candidate M cell and FAE receptor genes as
targets. We are currently developing several candidate formulations
for testing in preclinical experiments using mouse models.
We are focusing on influenza, since significant market need
exists for targeted mucosal vaccines against emerging strains
of influenza. We anticipate that initial preclinical studies
will be underway by the end of 2005, and will yield key information
on the potency of the recombinant vaccine formulations.
Animal Health Applications
Neurome’s vaccine technology may also be applied to
homologous receptors in additional animal species, specifically
those in important veterinary medicine markets, such as farm
animals (chickens, pigs, cows, sheep), horses, and pets such
as cats and dogs. The direct benefit to veterinary medicine
includes ease of use, and a reduction in the dependency on
low-dose antibiotic use.
The worldwide market for vaccines is estimated to grow to
between $10 and $20 billion in the next five years. Currently
available vaccines are targeted to only a small proportion
of known infectious agents. Moreover, the technology presently
used in vaccine development has not advanced in over sixty
years. Present barriers to development of new vaccines include
challenges in the cultivation of the infectious agents themselves
for extraction of antigens, limited knowledge toward identification
of the most immunogenic (and protective) components of the
infectious agents, and development of optimal formulations
of antigen and adjuvant for effective immunization. Neurome’s
vaccine technology addresses these challenges, and provides
an opportunity for rapid development of a new class of mucosal
vaccines, targeted against a wide variety of infectious agents.