Strike Pharma is applying proprietary Adaptable Drug Affinity Conjugate (ADACTM) technology to develop clinically-relevant candidates for the treatment of solid tumors. Tumor-associated antigenic peptide cargoes affinity-linked to preselected agonistic antibody carriers will create immunotherapeutic candidates with improved efficacy to:
- Enable the immune system to recognize and attack tumor cells
- Generate a functional ‘immune surveillance’ system to destroy metastases and provide a lasting immune response.
- Avoid the need for expensive, highly specialized ex-vivo procedures – in vivo development
Designed to stimulate an immune response within the body to attack cancer cells and thereby strengthening the body’s natural defences, these therapeutic treatments ‘teach’ the immune system to recognize tumor-associated antigens (usually peptides or proteins) that are not found or are at very low levels in normal cells. The immune system can then react to these antigens and destroy the cancer cells.
Current antibody and peptide immunotherapeutics often lack sufficient efficacy while cell-based therapies, although more successful in stimulating the body’s immune system, involve cumbersome and expensive ex-vivo procedures.
Strike Pharma’s initial focus is therefore to use proprietary ADAC technology to develop novel immunotherapeutics for the treatment of solid tumors, linking synthetic, neoantigenic peptide cargoes (previously identified in solid tumors) to well-characterized CD40 agonistic antibody carriers.
Preliminary studies have demonstrated:
- Retained agonistic activity of antibody
- 20-fold increase in peptide stability
- Enhanced activation of immune system as indicated by T-cell activity in vivo and in vitro
How it works: ADAC technology links a tumor-associated antigenic peptide ‘cargo’ to an agonistic CD40 antibody ‘carrier. The CD40 agonistic antibody boosts the immune response to tumor antigens by activating dendritic, antigen-presenting (APC) cells which, in turn, activate T-cells. Correct presentation of the antigen-antibody complex to the APC cells ensures that the APCs are recognized by T-cell lymphocytes, thereby promoting activation of anti-tumor T-cells and ‘re-educating’ macrophages to destroy cancerous cells. These T-cells will continue to be produced in the patient’s body thereby improving overall efficacy.
Proprietary Adaptable Drug Affinity Conjugate (ADAC) technology is used to affinity-link synthetic, neoantigenic peptide cargoes, previously identified in solid tumors, to well-characterized CD40 agonistic antibody carriers.
The design flexibility when linking carrier to cargo via an affinity-based interaction opens up many new opportunities.
- Develop highly targeted, truly individualized treatments
o Use any antigenic peptide based on the genetic profile of each patient’s tumor - Enhance immunomodulation effects
o Correctly present the antigen-antibody complex for efficient delivery to dendritic APC cells thereby ensuring T-cell activation - Improve pharmacokinetic properties due to improved peptide stability
o Minimizing toxicity risk - Reduce dosage requirements – highly targeted immunotherapeutic with an extended half-life
- Contribute to improving cost-effectiveness for each treatment:
o Requires lower dosages – smaller scale production - Transfer smoothly through clinical trials
o No need to re-approve CD40 agonistic antibody carrier – change only the synthetic peptide
Why affinity?
Conventional chemical conjugation methods, used to link a ‘carrier’ antibody to its ‘cargo’ (a cytotoxic drug) for development of antibody-drug candidates (ADCs), present several challenges when trying to conjugate a biomolecule such as an antigenic peptide. Limits in design flexibility and instability of the peptide cargo are just two issues that can lead to sub-optimal efficacy. In addition, with each new peptide (neoantigen) comes the challenge of optimizing conditions to ensure production of a stable vaccine in the most suitable formulation to facilitate in vivo delivery to dendritic cells.
How it works: Synthetic, neoantigenic peptide cargoes, previously identified in solid tumors, are linked to well-characterized CD40 agonistic antibody carriers via a universal, non-immunogenic peptide tag (pTag).
The CD40 protein is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily of cytokine receptors characterized by the ability to bind tumor necrosis factors (TNFs). Several TNF receptors are primarily involved in apoptosis (programmed cell death) and inflammation, but they can also take part in other signal transduction pathways, such as proliferation, survival, and differentiation. CD40 plays a critical role in T cell-dependent humoral immune responses. The protein is also found in other cell types such as monocytes and dendritic cells. Also widely expressed is the CD40-ligand (CD40-L/CD154), a member of the TNF family, suggesting that CD40-CD40-L interactions play a significant role in immune regulation. Numerous CD40 agonist antibodies with different profiles, epitope binding properties, Fc regions etc. have been evaluated in the clinic and found to be tolerable and feasible. Administration is associated with mild to moderate (but transient) cytokine release syndrome, indicating that their full agonistic effect could be limited by acceptable dosing levels.