Over 100 years ago, Nobel laureate Paul Ehrlich imagined the ideal therapeutic: a “magic bullet,” which linked a highly-toxic chemical to a molecule targeted to invading cells. This conjugate of a specific targeting molecule and highly destructive payload would act like a missile delivering a fatal strike directly to the disease without harming the patient. The advent of antibody-drug conjugates (ADCs), which combine the high specificity of monoclonal antibodies with potent chemotherapies, sets the stage for the concept of Paul Ehrlich's magic bullet to be realized.
ADCs are three-part bioconjugates comprising an antibody targeting molecule, a toxic payload, and a linker to connect them. Key features of each of these components contribute to the specificity and activity of these bioconjugates.
- Monoclonal antibodies (Mab)
- Specific receptor binding
- MAb-receptor complex internalization in the cell
- Well-characterized manufacturing and purification
- Differential target receptor expression can distinguish between healthy and cancer cells
- Protein engineering can introduce novel amino acids to control linker/toxin conjugation
- Stable MAb-toxin linkage until internalized in the cell
- Choice of cleavable or non-cleavable linkers
- Cleavable linkers are stable in the systemic circulation, but can be cleaved under intracellular conditions in a strong acidic environment with digestive enzymes, preferably without the toxin leaking back into the circulation
- Non-cleavable linkers depend upon intracellular degradation amino acid by amino acid until the toxin is activated.
- Can be suited to the toxin action and chemistry of the MAb
- Highly potent toxins
- Inhibit intracellular processes necessary for cell survival (for example, mitosis and DNA replication), but are not active outside the cell
Igenica’s SNAP technology can leverage attributes of all three components of an ADC. Target identification and antibody selection that yield differential binding to cancer cells is a prerequisite for ADC safety and efficacy. SNAP uses native MAb proteins produced by well-established manufacturing processes and simple chemical conjugation without site-directed mutagenesis of the antibody, reducing cost and potential risk of altered pharmacokinetics and immunogenicity. Igenica also has the capability to engineer site-specific amino acid changes in the MAb to enable flexibility in choice of linkers and toxins. Igenica has proprietary linkers, MAbs and toxins to produce unique ADCs, but also the expertise to combine their MAbs with conventional linkers and toxins to optimize ADC creation with the goal of delivering on the promise of the magic bullet.