Breakthrough Clinical Results

Bolt Biotherapeutics announced preclinical results for its next-generation Boltbody™ ISACs targeting CEA and PD-L1 at the AACR Annual Meeting 2025. The CEA-targeted ISAC showed complete responses in mice and was well-tolerated in non-human primates (NHPs). The PD-L1 ISAC demonstrated a unique mechanism of action, directly activating and reprogramming PD-L1-expressing myeloid cells to drive complete responses and immunological memory, even in models resistant to conventional PD-1/PD-L1 blockade. Both ISACs utilize a tumor-targeting antibody conjugated to a TLR7/8 agonist, stimulating immune responses and showing potential for durable therapeutic effects. These findings suggest promising new approaches for treating cancers expressing CEA and PD-L1.

Emerging Mechanism of Action

Colorectal cancer (CRC) is a complex disease with multiple molecular mechanisms driving its development and progression. Based on PubMed publications over the past three years, several key mechanisms of action (MoAs) are emerging as important targets for therapeutic intervention:

1. Genetic and Epigenetic Alterations:

2. Genomic Instability: CRC arises from the accumulation of genetic and epigenetic alterations in oncogenes, tumor suppressor genes, and DNA repair genes. Chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) are major pathways involved in CRC development. Specific gene mutations, such as those in APC, KRAS, BRAF, PIK3CA, PTEN, and DNA mismatch repair genes, play crucial roles in CRC initiation, progression, and metastasis. These mutations dysregulate signaling pathways, leading to uncontrolled cell proliferation, survival, invasion, and migration.

3. Epigenetic Changes: Aberrant DNA methylation, microRNA (miRNA) deregulation, and alterations in histone modification states are also implicated in CRC. These epigenetic changes can silence tumor suppressor genes or activate oncogenes, contributing to tumor development and progression.

4. Signaling Pathways:

5. Wnt/β-catenin Signaling: This pathway is frequently activated in CRC, leading to increased cell proliferation and survival. Mutations in APC, a key regulator of the Wnt pathway, are common in CRC.

6. MAPK/ERK Signaling: This pathway is also often dysregulated in CRC, contributing to cell growth and survival. Mutations in KRAS and BRAF, components of the MAPK pathway, are frequent in CRC and can lead to resistance to targeted therapies.
7. PI3K/Akt/mTOR Signaling: This pathway is involved in cell growth, survival, and metabolism. Mutations in PIK3CA and PTEN, components of the PI3K pathway, are found in CRC and can contribute to tumor development and progression.
8. TGF-β Signaling: This pathway normally inhibits cell growth, but it can be suppressed or altered in CRC, promoting tumor progression and metastasis.

9. STAT3 Signaling: STAT3 is a transcription factor that is often overexpressed and persistently activated in CRC cells. It plays a prominent role in CRC initiation, progression, and metastasis, and contributes to chemoresistance.

10. Tumor Microenvironment:

11. Angiogenesis: The formation of new blood vessels is essential for tumor growth and metastasis. VEGF signaling plays a major role in CRC angiogenesis, and anti-angiogenic therapies targeting VEGF or its receptors have shown clinical benefit.

12. Immune Evasion: CRC cells can evade the immune system through various mechanisms, including downregulation of MHC molecules, secretion of immunosuppressive cytokines, and recruitment of immunosuppressive cells. Immunotherapy approaches, such as immune checkpoint inhibitors, aim to overcome these mechanisms and enhance antitumor immunity.

13. Gut Microbiome: The gut microbiome plays an important role in CRC development. Dysbiosis, or an imbalance in the gut microbial community, can promote inflammation, DNA damage, and tumorigenesis. Specific bacterial species, such as Fusobacterium nucleatum, have been linked to CRC development and progression.

14. Metabolic Reprogramming:

15. Altered Cellular Metabolism: CRC cells reprogram their metabolism to support rapid proliferation. This includes increased glycolysis, glutaminolysis, one-carbon metabolism, and fatty acid synthesis. These metabolic changes can be targeted therapeutically.

16. Other Emerging Mechanisms:

17. Epithelial-Mesenchymal Transition (EMT): This process allows cancer cells to acquire invasive and metastatic properties. EMT is regulated by various signaling pathways and transcription factors, and it can be targeted therapeutically.

18. Cancer Stem Cells (CSCs): These cells are thought to be responsible for tumor initiation, metastasis, and resistance to therapy. CSCs have unique properties, such as self-renewal and differentiation, and they can be targeted therapeutically.

Understanding these MoAs is crucial for developing new and improved therapies for CRC. Ongoing research is focused on identifying new targets within these pathways and developing more effective and personalized treatment strategies.

Drug used in other indications

CEA (Carcinoembryonic antigen) is being investigated as a target for various cancer immunotherapies, including trials for colorectal cancer and other CEA-expressing solid tumors. While the provided text doesn't specify other cancer types explicitly being targeted by CEA Boltbody™ ISAC beyond colorectal cancer, it does mention other CEA-targeted therapies being explored, such as:

• Bispecific antibodies (BsAbs): These antibodies bind to both CEA and a second target, such as a cytotoxic agent or immune cell. They are being investigated for radioimmunotherapy and imaging.
• Bispecific T-cell engagers (BiTEs): These molecules redirect T cells to CEA-expressing tumor cells, promoting their destruction.
• Chimeric antigen receptor T cells (CAR-T): This approach involves engineering T cells to express a chimeric antigen receptor that recognizes CEA, enhancing their ability to target and kill CEA-positive cancer cells.

The provided text also mentions immune-stimulating antibody conjugates (ISACs), which combine a tumor-targeting antibody with an immunostimulatory agent. One example given is NJH395, a TLR7 agonist conjugated to an anti-HER2 antibody. While this specific ISAC targets HER2, the concept of ISACs could be applied to CEA as well, suggesting that a CEA-targeted ISAC is a plausible therapeutic approach.

Intervention models for these trials would likely involve systemic administration of the therapeutic agent (BsAb, BiTE, CAR-T, or ISAC). The specific model would depend on the agent being used. For example, CAR-T cell therapy involves collecting a patient's T cells, engineering them to express the CEA-specific CAR, and then infusing them back into the patient. BsAbs, BiTEs, and ISACs would likely be administered intravenously.

It's important to note that the development of these therapies is ongoing, and the specific cancer types and intervention models being investigated may change as research progresses. More information on specific trials can be found on clinicaltrials.gov or other clinical trial registries.

Company drugs in pipeline

Bolt Biotherapeutics is developing immune-stimulating antibody conjugates (ISACs), which combine a TLR7/8 dual agonist with tumor-targeting antibodies. One of their lead ISACs targets HER2, a protein commonly overexpressed in certain types of breast cancer. While the provided text focuses on the mechanism of action and preclinical results of the HER2-targeted ISAC, it suggests that this platform technology could be applied to other tumor types by conjugating the TLR7/8 agonist to antibodies targeting different tumor antigens. Therefore, while breast cancer is the primary indication mentioned, the platform's potential extends to other cancers for which suitable antibody targets exist. The text does not explicitly name these other potential indications.