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Advancing of TME science-Targeting anti-CTLA4 in CT26 plus SIRPa reducing CD473 new Manocept advanced constructs now presented in 2022..plus others disclosed on dox moving towards 2024 IND's Oct 2022 The abstract, “Synthetic CD206 Targeted Constructs Carrying Paclitaxel
or Novel Bisphosphonate Payloads Alter Macrophages Towards
Pro-inflammatory Phenotypes; The Paclitaxel Construct Improves the
Efficacy of anti-CTLA4 in CT26 Tumors” (Abstract #1161), will be
presented as a poster on November 10, 9 am to 9 pm in the conference
center’s poster hall. Further details of the abstract will be announced
in a future press release once the meeting embargo is lifted.
Interpretation: Possibly targeting the improvement of PD1/check point inhibitors in colorectal carcinoma in mouse/murine testing PD-1 is a checkpoint protein on immune cells called T cells.
It normally acts as a type of “off switch” that helps keep the T cells
from attacking other cells in the body. It does this when it attaches to
PD-L1, a protein on some normal (and cancer) cells How does CTLA-4 participate in tumor cell recognition? A protein found on T cells (a type of immune cell) that helps keep the body's immune responses in check. When CTLA-4 is bound to another protein called B7, it helps keep T cells from killing other cells, including cancer cells. Some anticancer drugs, called immune checkpoint inhibitors, are used to block CTLA-4. Preclinically, the
murine CT26 colon carcinoma line has become a platform model for
evaluating the potential of drug combinations with immune checkpoint
inhibitor antibodies. It is a highly immunogenic tumor and tends to show objective response rates to a number of commercially available checkpoint inhibitors. May 2022 The poster will present information related to the synthesis of two
novel bisphosphonate drugs that have been attached to Navidea’s
CD206-targeted drug delivery platform molecule, Manocept. These
constructs use a novel degradable linker to release the therapy only
once they have been internalized into a CD206-expressing cell, such as a
tumor associated macrophage. The new therapeutic constructs were
evaluated in human macrophage cell culture assays to compare the ability
of the new constructs with unbound free therapy to shift the phenotype
of macrophages toward a proinflammatory gene expression pattern. The new
drug delivery constructs successfully shifted the phenotypes of human
macrophages towards a proinflammatory state and compared favorably to
the unbound free therapy. The new drug constructs also induced a highly
significant reduction in macrophage expression of signal regulatory
protein alpha (“SIRPα”), the receptor for the “don’t eat me” signal
that, when activated, suppresses the ability of macrophages to attack
and phagocytize disease associated cells such as cancer cells. The
ability to induce this type of phenotypic change in macrophages could
have far-reaching applications in cancer immunotherapy.
Interpretation in layman's terms of the PR on SIPRa Manocept constructs significantly reduced SIPRa activation/over
expression
on macrophages associated with tumors/cancer,
which reduced the do not eat me CD 47 signal to the macrophages which
signalling stops macrophages from the normal phagocytosis (eating
cancer) process. So in summary, by
reducing the SIPRa activation/over expression the macrophages were not
signaled to not eat the cancer cells,
so the Manocept constructs were
able to alter the macrophages to the eat me state for phagocytosis to
start. Will be exciting to see them publish results of the phagocytosis process when the actual eat me state is in progress. |
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