Tumor-Associated Macrophages: BDC-3042 Animal Model Dr. Kenkel SITC 2022
What are tumor-associated macrophages?
Our antibody that we refer to as BDC-3042 targets a molecule known as Dectin-2. This is a potent immune-activating receptor expressed by tumor-associated macrophages, or TAMs, across various types of human solid tumors. Dectin-2 is best known for its role in pathogen recognition and for stimulating immune responses against foreign pathogens. But here we’re actually trying to leverage this expression by TAMs to stimulate an immune response against the cancer rather than against some foreign pathogen. And we are targeting these TAMs using our antibody, which specifically binds to and agonizes Dectin-2.
This then stimulates proinflammatory signaling in the TAMs that ultimately converts them into cells that promote, rather than suppress, various mechanisms of antitumor immunity.
What Are The Study Findings That Support Dectin-2?
Overall the data we presented in our SITC poster show the key reasons why we think Dectin-2 is such a promising new target for immuno-oncology. We show various pieces of data that demonstrate the therapeutic potential of our agonist antibody against Dectin-2. For example, we showed that Dectin-2 is expressed by TAMs across various types of human solid tumors and that our antibody, BDC-3042, can selectively bind to those TAMs in the human tumor samples and activate them, resulting in the secretion of various proinflammatory cytokines, chemokines, cytotoxic mediators that all can help to promote anti-tumor responses.
Also, very importantly, we showed that, while Dectin-2 can be highly expressed by TAMs, its expression is relatively low on immune cells in peripheral blood as well as in most normal human tissues on a whole tissue level. We also showed that, consistent with the low expression of the target in blood, we see very little activation of cells in our whole blood-based in vitro assays.
Overall, we think that this restricted expression pattern of Dectin-2 is a really important factor enabling us to administer our antibody systemically to target tumors throughout the body rather than just locally as other immune agonists have been in the clinic.
Watch and Share the Video Here: https://oncologytube.com/v/41523
What Is The Preclinical Animal Model Design?
To enable us to directly evaluate our human Dectin-2 antibody in vivo, we use mice with humanized immune systems. Basically, these mice are generated using human hematopoietic stem cells or HSCs that are transplanted into immunodeficient mice. And then, over a period of time these human HSCs give rise to multiple human immune cell lineages including T-cells, B-cells and very importantly also monocytes, which are cells that are recruited from the blood into the tumor and that give rise to those TAMs. Because myeloid cell engraftment in the humanized mice can be fairly poor at times, at least in the most basic models, we use a combination of a particular, transgenic mouse strain and human tumor model that both provide for better myeloid cell engraftment both peripherally as well as locally within the tumor, in the form of those TAMs.
We found that, using this model, we can consistently get a sizeable population of human, Dectin-2 expressing TAMs that we can use to target and modulate with our antibody.
5 Key Takeaways about Tumor Associated Macrophages (TAMs)
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Tumor-associated macrophages (TAMs) are the main immune cell population in the majority of malignancies due to their immunosuppressive effects on the tumor microenvironment (TME).
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Using naturally generated ligands, antagonism of Dectin-2 on TAMs induces effective anti-tumor immunity in syngeneic animal tumor models. As a unique approach to myeloid-directed immunotherapy, we created a human Dectin-2-targeted agonistic antibody, BDC-3042, which is capable of robustly activating TAMs.
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The expression of Dectin-2 was evaluated using flow cytometry, immunohistochemistry, and public databases. BDC-3042 was used to stimulate human whole blood, monocyte-derived macrophages, and single-cell cultures from dissociated human malignancies overnight.
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Dectin-2 is expressed by tumor-associated macrophages (TAMs) in numerous tumor types, including breast, colon, and lung malignancies, but its expression is modest in most normal tissues. BDC-3042 binds with nanomolar affinity to recombinant Dectin-2 and Dectin-2-expressing cells.
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The current data illustrate the therapeutic potential of targeting Dectin-2 on TAMs with the agonistic antibody BDC-3042 as an unique pan-cancer strategy for myeloid cell-directed tumor immunotherapy.
What Are Some Of The Key Data Points?
We evaluated the antitumor efficacy of BDC-3042 across multiple cohorts of mice using distinct human HSC donors. We think this is important to use multiple HSC donors for these kinds of mouse models because this helps to capture some of the heterogeneity we are likely to encounter in the clinic ultimately.
And as we showed in our poster, our antibody exhibited antitumor activity across these multiple cohorts of mice, and very importantly, our antibody generally performed better than the PD-1 blocker Pembrolizumab, which we use as a benchmark molecule and which of course has been used very successfully in the clinic.
And finally we showed some of the pharmacodynamic changes associated with treatment with our antibody, showing that our antibody elicits an influx of human immune cells, changes in activation markers on macrophages that are consistent with the proinflammatory reprogramming of the cell types, as well as some favorable changes in the T-cell compartment that are indicative of a more robust antitumor immune response.
Will BDC-3042 Be Tested in a Clinical Trial?
Currently we are in IND-Enabling studies and things are progressing well there. And we are planning to enter the clinic in 2023, next year.
Final Thoughts for the Tumor-Associated Macrophages Clinical Trial
We just want to convey how encouraged we are by the data generated to date and how excited we are about this new target and this new approach for cancer immunotherapy, and we are very hopeful about the positive impact this can make on patients’ lives ultimately, once we get into the clinic.
Justin A. Kenkel, PhD – About The Author, Credentials, and Affiliations
The position of Principal Scientist of Bolt Biotherapeutics, Inc. currently belongs to Dr. Justin A. Kenkel. His doctorate in immunology was awarded to him in the year 2014. He was performing research in the field of immunology while he was a graduate student at the School of Medicine at Stanford University. In 2018, he graduated from the postdoctoral program he had been attending in pathology.
Reference
BMJ Journals – 1348 BDC-3042: A Dectin-2 agonistic antibody for tumor-associated macrophage-directed immunotherapy. BMJ Journals, November 2022