Molecular Templates has created vast libraries of ETBs by embedding random targeting domains into bacterial toxin scaffolds. Each ETB has a distinct binding affinity but retains the biologically active properties of the parent toxin. ETBs are capable of targeting validated therapeutic cell surface receptors but also non-traditional targets that cannot be therapeutically targeted by antibodies or small molecules.
Molecular Templates has successfully developed a lead ETB (MTI-SAM3) against an undisclosed receptor present on certain melanoma cells. MTI-SAM3 exhibits an LD50 in the nM concentration range against melanoma cells but is inactive against cells of other etiologies. MTI-SAM3 retains the predictable PK/PD profile of the parent toxin and was discovered through an etiology-based screen in which the target was not specified. Molecular Templates anticipates entering clinical studies with MTI-SAM3 in the near future.
| Antibodies | Immunotoxins | ETBs | |
|---|---|---|---|
| Screening Metric | Binding affinity | Binding affinity of targeting domain | Direct cell-kill [a] |
| Target ID a priori | Required | Required | Not required [b] |
| Mechanism of Action | Target binding | Direct cell-kill | Direct cell-kill |
| Target Specificity | Very high (nM to pM) | High (nM) | High (nM) [c] |
| Size | ~150 kd | ~60 kd | ~20kd |
| Half-Life | Days to weeks | Minutes to days | Minutes to days [d] |
| PK/PD | Established | Established | Established [e] |
| Other Scaffold Properties | Receptor mediated internalization | Forced internalization; Intracellular routing | Forced internalization; Intracellular routing; Antigen presentation |
[a] ETBs are screened on cell-killing ability that involves its ability to bind a target, internalize, and route itself intracellularly.
[b] Because ETBs are selected on cell-kill, etiology based screens can be performed without knowing the target beforehand.
[c] A different standard applies to ETBs given their unique features and high affinity does not correlate to cell kill specificity or potency.
[d] ETBs can be manipulated to extend half life in the event it is optimal for particular disease indications.
[e] ETBs share the same pharmcokinetic and pharmacodyanmics as the parent toxin scaffold making them predictable.