Approach

The majority of the current immunotherapy approaches are focused on the adaptive immune response. Bolt is seeking to successfully engage the innate immune system that will ultimately trigger the adaptive immune system to generate a robust anti-tumor immune response.

Myeloid cells are a group of immune cells that belong to the innate immune system, consisting of cell types known as monocytes, macrophages, dendritic cells, and granulocytes. These cells serve various essential roles in the body’s immune system. They are critically involved in the regulation of T cell responses, bridging our body’s innate and adaptive immune systems. Due to various immunosuppressive factors produced in the tumor microenvironment, the normal function of these cells can be inhibited, limiting their ability to create a productive anti-tumor immune response.

When functioning properly, myeloid cells can stimulate anti-tumor effects in the body, including direct tumor cell killing as well as activation of tumor-specific T cells to support durable anti-tumor immune responses and immunological memory. Activated myeloid cells also secrete pro-inflammatory chemokines and cytokines that recruit additional immune effector cells and help convert immunologically “cold” tumors into “hot” tumors. As such, these normally tumor-supportive myeloid cells can be converted to tumor-destructive myeloid cells that amplify innate and adaptive immune responses, leading to productive anti-tumor immunity.

Boltbody™ ISAC Platform

Our Boltbody immune stimulating antibody conjugate (ISAC) approach is pioneering a new category of immunotherapies that combines the precision of antibody targeting with the strength of the innate and adaptive immune systems. By activating and recruiting myeloid cells, Boltbody ISACs re-program the tumor microenvironment to invoke a new anti-tumor immune response.

Our Boltbody ISACs are delivered systemically but act locally in the tumor microenvironment by triggering a localized anti-tumor immune cascade. This process enables the patients’ own immune system to determine which are the relevant T cells to mobilize for tumor destruction and subsequent immunosurveillance, demonstrating how an off-the shelf Boltbody immunotherapeutic can deliver a personalized therapeutic outcome. We believe that the development of systemic immunological memory will result in long-term anti-tumor responses.

Unlike immuno-oncology approaches that seek solely to relieve immune suppression, Boltbody ISACs act by reengaging the immune system to become an active participant in the cancer immune cycle. The following key features provide us with the opportunity for robust applications across various solid tumors designed to deliver potent, safe, and durable therapeutics:

  • Ability to address difficult-to-treat solid tumors including those refractory to current treatments;
  • Engaging the body’s innate and adaptive immune response;
  • Generation of immunological memory to provide long-term anti-tumor responses and guard against recurrence;
  • Capability to modulate myeloid cell activity via TLR potency and selectivity and Fc engineering;
  • Well tolerated in preclinical studies by avoiding unintended systemic immune stimulation; and
  • Potential to benefit patients that have defective adaptive immune response.

We designed our Boltbody ISACs with three primary components: a tumor antigen-targeting antibody, a linker that can be designed either as cleavable or non-cleavable, and a proprietary immune stimulant to activate the patient’s innate and adaptive immune system. Together these components allow our Boltbody ISACs to overcome the limitations of existing immunotherapies by triggering both the body’s innate and adaptive immune systems through different stages of the cancer immunity cycle to produce long-term anti-tumor activity.

View Publications

Boltbody™ ISAC Platform

Our Boltbody immune stimulating antibody conjugate (ISAC) approach is pioneering a new category of immunotherapies that combines the precision of antibody targeting with the strength of the innate and adaptive immune systems. By activating and recruiting myeloid cells, Boltbody ISACs re-program the tumor microenvironment to invoke a new anti-tumor immune response.

Our Boltbody ISACs are delivered systemically but act locally in the tumor microenvironment by triggering a localized anti-tumor immune cascade. This process enables the patients’ own immune system to determine which are the relevant T cells to mobilize for tumor destruction and subsequent immunosurveillance, demonstrating how an off-the shelf Boltbody immunotherapeutic can deliver a personalized therapeutic outcome. We believe that the development of systemic immunological memory will result in long-term anti-tumor responses.

Unlike immuno-oncology approaches that seek solely to relieve immune suppression, Boltbody ISACs act by reengaging the immune system to become an active participant in the cancer immune cycle. The following key features provide us with the opportunity for robust applications across various solid tumors designed to deliver potent, safe, and durable therapeutics:

  • Ability to address difficult-to-treat solid tumors including those refractory to current treatments;
  • Engaging the body’s innate and adaptive immune response;
  • Generation of immunological memory to provide long-term anti-tumor responses and guard against recurrence;
  • Capability to modulate myeloid cell activity via TLR potency and selectivity and Fc engineering;
  • Well tolerated in preclinical studies by avoiding unintended systemic immune stimulation; and
  • Potential to benefit patients that have defective adaptive immune response.

We designed our Boltbody ISACs with three primary components: a tumor antigen-targeting antibody, a linker that can be designed either as cleavable or non-cleavable, and a proprietary immune stimulant to activate the patient’s innate and adaptive immune system. Together these components allow our Boltbody ISACs to overcome the limitations of existing immunotherapies by triggering both the body’s innate and adaptive immune systems through different stages of the cancer immunity cycle to produce long-term anti-tumor activity.

View Publications

Myeloid Modulator Platform

Our Myeloid Modulator Platform reawakens myeloid cells to attack tumor cells. We identified monoclonal antibodies that are capable of binding to and agonizing a novel cell surface protein (referred to as TAM1) on tumor-supportive macrophages. The activation of these macrophages results in the production of pro-inflammatory cytokines, consistent with the characteristics of tumor-destructive macrophages. TAM1 may have the potential to reprogram tumor-supportive macrophages into tumor-destructive macrophages to elicit a productive anti-tumor immune response. Additionally, KRAS and TP53 mutations may upregulate TAM1 on tumor-associated myeloid cells and could provide an avenue to develop precision medicine with an immune modulator.

More About Myeloid Cells

Myeloid cells belong to the innate immune system and largely consist of cell types known as monocytes, macrophages, dendritic cells, and granulocytes. These cells are best known for their ability to detect, destroy, or assist in triggering an adaptive immune response to infectious microorganisms and viruses. They also are increasingly recognized to play a key role in anti-tumor immunity. As professional antigen-presenting cells (APCs), macrophages and dendritic cells in particular are critical for the induction of antigen-specific T cell responses and thereby bridge our body’s innate and adaptive immune systems. Enabled by the expression of an array of pattern recognition receptors (including TLRs, etc.) that bind to molecules present on microbes or viruses, myeloid APCs are equipped to recognize pathogens and potentially cancerous cells and initiate appropriate antigen-specific immune responses.

While myeloid APCs have the potential to present tumor antigens and expand tumor-specific T cells, various factors present in the tumor microenvironment can suppress their activity and convert them into immunosuppressive cell types that inhibit T cell responses and fuel tumor growth. However, these immunosuppressed myeloid cells can be transformed into effective APCs with the use of certain immune stimuli, such as the TLR7/8 agonists used in Boltbody ISACs. When appropriately activated by a Boltbody ISAC or other stimuli, the myeloid APCs can migrate to lymph nodes where they mediate the activation and rapid expansion of tumor-reactive T-cells. These activated myeloid APCs also secrete pro-inflammatory chemokines and cytokines that recruit more immune effector cells to the tumor microenvironment and enhance their tumor-killing activity. Thus, by acting at the level of the tumor antigen uptake and presentation, myeloid-directed therapies like Boltbody ISACs have the potential to generate anti-tumor T cell responses and address difficult-to-treat solid tumors, including those refractory to current treatments.