Conjugates with reduced adverse systemic effects
A conjugate of an active agent and a targeting moiety having affinity for a target cell, in which the active agent has been modified by attachment of a cell membrane-impermeabilizing group so that, if the active agent so modified is cleaved from the conjugate in the blood plasma instead of inside the target cell, the cell membrane-impermeabilizing group prevents or limits entry of the modified active agent into cells, thus reducing its systemic or non-specific adverse effects, including toxicity.
1. A conjugate having a structure according to one of formulae X, XI, or XII:
wherein
AA 1 is a lysine, arginine, or citrulline amino acid side chain residue;
AA 2 is a phenylalanine, valine, alanine, leucine, or isoleucine amino acid side chain residue;
p in formulae X to XII is an integer from 1 to 6;
q in formulae X to XII is an integer from 1 to 5;
r in formulae X to XII is an integer from 1 to 5;
—C(═O)LMB in formulae X to XII is a leptomycin B residue, having the structure
x ⊖ in formulae X to XII is a pharmaceutically acceptable counteranion; and
mAb is a monoclonal antibody.