Immune stimulating antibody conjugate explained

An Immune stimulating antibody conjugate is a monoclonal antibody that conjugates an antibody to an immune-stimulatory agent.[1] They have been used in targeting tumors in mouse models, particularly to turn "cold tumors into hot ones".[2] Immune stimulating antibody conjugates work by activating dendritic cells within the tumor,[3] and are capable of being delivered systemically.[4] With some patients being resistant to checkpoint inhibitors, immune stimulating antibody conjugates may be able to harness an immune response generated through the stimulation of toll-like receptors.[3] In mice models, "dendritic cells (DCs) [were able] to internalize tumor antigens and subsequently activate tumor-reactive T cells"; this has been used "to treat autologous and autochthonous tumors successfully".[5]

Example

An immune stimulating antibody conjugate comprising a TLR7/TLR8 dual agonist conjugated to antibodies targeting at human epidermal growth factor receptor 2(HER2) has been developed.[6] Mechanically, immune stimulating antibody conjugates required tumor antigen recognition, FcγR-dependent phagocytosis and TLR-mediated activation to drive tumor killing by myeloid cells and subsequent T-cell-mediated antitumor immunity.

See also

Notes and References

  1. Web site: Study to Determine Safety and Dose of NJH395 in Non-breast HER2+ Advanced Cancer . . 9 June 2019 . English . 2018 . Immune stimulator antibody conjugate (ISAC), consisting of a monoclonal antibody which targets HER2 conjugated to an immune-stimulatory agent..
  2. Web site: Vinluan F . Bolt Bio Bags $54M for Drugs that Turn the Heat Up on "Cold" Tumors . . 9 June 2019 . English . 5 February 2019. The company’s therapies consist of a tumor-targeting antibody that homes in on tumors and is paired with an immune stimulant that turns cold tumors into hot ones. In preclinical testing, the company says that these immune-stimulating antibody conjugates eliminated tumors..
  3. Web site: Grover N . AACR: Bay Area biotech bets on antibodies armed with immuno-stimulant to fight checkpoint-resistant cancers . Endpoints News . 9 June 2019 . English . 1 April 2019. The researcher, Stanford’s Ed Engleman, has built on his research into dendritic cells — which are considered ‘sentinels’ of the immune system as they are responsible for inducing immune T-cell responses — to develop this Immune-Stimulating Antibody Conjugate (ISAC) technology, which was unveiled by exclusive licensee Bolt Biotherapeutics at the American Association for Cancer Research (AACR) Conference on Monday. “What Bolt has come up with is to wake up dendritic cells within the (tumor) microenvironment, and we were able to do this in a targeted way,” said David Dornan, senior VP of research, in an interview with Endpoints News ahead of the conference. Many patients are refractory to checkpoint inhibitors because there are a number of immunosuppressive factors present in their tumor microenvironment, and so researchers have been trying to harness different molecules to stimulate the immune system, one of which are toll-like receptor (TLR) agonists — specialized proteins that initiate an immune response to foreign pathogens or, in this case, cancer cells. But the challenge of delivering these adjuvants is that they must be delivered intratumorally, because if they were administered systemically — say orally or intravenously — they can become toxic as immune cells across the body are activated and the impact is not targeted, Dornan emphasized..
  4. Web site: Week In Review: China Resources And Charoen Pokphand Join To Launch $300 Million Life Science Fund . . 9 June 2019 . English . 10 February 2019. Bolt is developing systemic immune system treatments to provide immunity-based therapies for cancer. The company will use the funds to advance its lead Boltbody™ Immune-Stimulating Antibody Conjugate (ISAC) into the clinic..
  5. Carmi Y, Spitzer MH, Linde IL, Burt BM, Prestwood TR, Perlman N, Davidson MG, Kenkel JA, Segal E, Pusapati GV, Bhattacharya N, Engleman EG . 6 . Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity . English . Nature . 521 . 7550 . 99–104 . May 2015 . 25924063 . 4877172 . 10.1038/nature14424 . 2015Natur.521...99C .
  6. Ackerman SE, Pearson CI, Gregorio JD, Gonzalez JC, Kenkel JA, Hartmann FJ, Luo A, Ho PY, LeBlanc H, Blum LK, Kimmey SC, Luo A, Nguyen ML, Paik JC, Sheu LY, Ackerman B, Lee A, Li H, Melrose J, Laura RP, Ramani VC, Henning KA, Jackson DY, Safina BS, Yonehiro G, Devens BH, Carmi Y, Chapin SJ, Bendall SC, Kowanetz M, Dornan D, Engleman EG, Alonso MN . 6 . Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity . Nature Cancer . 2 . 1 . 18–33 . January 2021 . 35121890 . 9012298 . 10.1038/s43018-020-00136-x .

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