Avid Bioservices Inc (CDMO)

[freethemice]

I have been thinking about how the understanding of the mechanism of action (MOA) for bavituximab has
evolved over the last decade. In the beginning the MOA was thought to be the destruction of the tumor
vasculature by macrophages which engaged the bavi antibodies bound to PS via the beta2-GP1 molecules on
the surface of the vascular endothelial cells. There was also an early understanding that exposed PS can be
immunosuppressive for macrophages and dendritic cells (DCs). Over time there has developed an understanding
in the cancer immunotherapy community that the tumor microenvironment is manipulated by the tumor
to a state which is advantageous to tumor survival, as you might expect. This shows up in the ratio of macrophages
which are in the M2 pro-tumor state versus the M1 anti-tumor state. This has now been extended to a similar
N2 to N1 ratio of neutrophils, and of DCs. This new knowledge of the tumor microenvironment changes
the understanding of the MOA for bavi. The central idea now is that the tumor establishes a microenvironment
that promotes its own survival, as you would expect from an evolutionary viewpoint. I now see the
main MOA of bavi as reversing this immunosuppressive microenvironment by the effect bavi has on macrophages.
I drew this figure before to show how this can happen when bavi binds to microvesicles (or exosomes)
or PS on the tumor vasculature.

Once this change has been effected from a pro-tumor microenvironment to an anti-tumor microenvironment
then the immune system is enabled to bring its full power to bear against the tumor. This entails the switching
from the M2 to the M1 state of macrophages ( and neutrophils and DCs), which then are enabled to phagocytose
(eat) the tumor endothelial cells which have PS exposed. So it is this switch which makes possible the initial
idea for bavi's MOA, that of destruction of the tumor vasculature. Dr. Thorpe talked of this in his NYAS webcast.
This switch also reduces the immunosuppression of the T cell response, that is the adaptive immunity arm, which
can lead to long-term immunity.
To me this change in emphasis of bavi's MOA leads to the idea that bavi can be used on more than just solid tumors.
The use on only solid tumors followed from the initial understanding of the MOA. Now we can see that the MOA is
much broader, that of reversing immunosuppression and awakening the total immune response to cancer.
This might mean that bavi could be useful in leukemia and lymphoma if there can be shown to be an immunosuppresive
environment that could be reversed by bavi. Perhaps these types of cancers also produce microvesicles to
thwart the immune response which can be neutralized by bavi. I hope you find this as interesting as I do.
FTM