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Abstract We have designed a heterodimerizing leucine zipper system to target a radionuclide to prelocalized noninternalizing tumor‐specific antibodies. The modular nature of the leucine zipper allows us to iteratively use design rules to achieve specific homodimer and heterodimer affinities. We present circular‐dichroism thermal denaturation measurements on four pairs of heterodimerizing leucine zippers. These peptides are 47 amino acids long and contain four or five pairs of electrostatically attractive g ↔ e′ (i, i′ +5) interhelical heterodimeric interactions. The most stable heterodimer consists of an acidic leucine zipper and a basic leucine zipper that melt as homodimers in the micro (T m = 28°C) or nanomolar (T m = 40°C) range, respectively, but heterodimerize with a T m >90°C, calculated to represent femtamolar affinities. Modifications to this pair of acidic and basic zippers, designed to destabilize homodimerization, resulted in peptides that are unstructured monomers at 4 μM and 6°C but that heterodimerize with a T m = 74°C or K d(37) = 1.1 × 10 −11 M. A third heterodimerizing pair was designed to have a more neutral isoelectric focusing point (pI) and formed a heterodimer with T m = 73°C. We can tailor this heterodimerizing system to achieve pharmacokinetics aimed at optimizing targeted killing of cancer cells.
Moll et al. (Thu,) studied this question.