1/ “Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy.” $PVCT thoughts: there’s no free lunch. A THREAD.
2/ 20Mar23: Endpoints: “BioNTech to pay $200M upfront in CTLA-4 antibody development, commercialization deal.” endpts.com/biontech-to-pa….
3/ The CTLA-4 asset BioNTech acquired is ONC-392. See here from #SITC21: jitc.bmj.com/content/jitc/9….
4/ The 2019 Nature article, ““Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy,” suggests that safer CTLA-4 agents can be developed by modifying the way in which the CTLA-4 receptor interacts with nature.com/articles/s4142…… twitter.com/i/web/status/1…
5/ #Yervoy (#ipilimumab) is limited to a maximum of 4 doses, whereas PD-1 is given continuously. Prescribing information: packageinserts.bms.com/pi/pi_yervoy.p….
6/ The authors are studying the modification of the fate of CTLA-4 receptors on the surface of cells upon complexing with anti-CTLA-4 antibodies, such as #ipilimumab (#Yervoy) and #tremelimumab (#Imjudo).
7/ Complexation of these agents with surface receptors causes endocytosis: the movement of the complexed receptors into the cell, and ultimately destruction of the complexed receptors by lysosomes, which is the normal mechanism by which cells destroy threats by “eating and… twitter.com/i/web/status/1…
8/ The 2019 Nature article authors indicate that this destruction leads to toxicity, presumably by triggering this process in non-target cells (e.g., in the gut, lungs, endocrine system, etc.) and producing undesirable downstream immune response against such cells.
9/ Their approach to avoid toxicity is to modify the receptor-antibody complex to render this complex labile once it enters the cell, so that the complex disassociates upon endocytosis but prior to lysosomal uptake and destruction. The intact receptor then migrates back to the… twitter.com/i/web/status/1…
10/ While the authors imply that this will maintain or enhance anti-tumor activity, it remains to be proven whether this is the case. For example, the same downstream signaling that leads to immune toxicity may have a role in anti-cancer activity.
12/ It appears that #ipilimumab (#Yervoy) and #tremelimumab (#Imjudo) lead to substantial or complete endocytosis of CTLA-4 receptors, whereas the modified systems largely keep these receptors intact.
13/ The implication could be that the authors’ approach reduces toxicity in non-target tissue but could also partially abrogate T cell activation that is the primary objective of the use of anti-CTLA-4 antibodies (#ipilimumab, #tremelimumab, etc.) in cancer.
14/ From Wikipedia: “CTLA-4 or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is upregulated in conventional T cells after activation – a en.wikipedia.org/wiki/CTLA-4… twitter.com/i/web/status/1…
15/ Thus, #ipilimumab and #tremelimumab complex CTLA-4 on T cells, cancelling the downregulation of an activated T cell (CTLA-4 acts like a trigger safety on a loaded gun, and Ipi or Treme block this safety mechanism, allowing the weapon to fire).
16/ By modifying the fate of the CTLA-4-receptor + CTLA-4-receptor-blocking-antibody, the authors’ approach may interfere with the anti-cancer activity of the anti-CTLA-4 antibody. THREAD END.
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