Abstract: The present invention provides analogues of duocarmycins that are potent cytotoxins. Also provided are peptidyl and disulfide linkers that are cleaved in vivo. The linkers are of use in forming prodrugs and conjugates of the cytotoxins of the invention as well as other diagnostic and therapeutic moieties. The invention provides prodrugs and conjugates of the duocarmycin analogues with the linker arms of the invention.

Abstract: The prodrug of the invention is a modified form of a therapeutic agent and comprises a therapeutic agent, an oligopeptide, a stabilizing group and, optionally, a linker group. The prodrug is cleavable by the enzyme Thimet oligopeptidase, or TOP. Also disclosed are methods of designing prodrugs by utilizing TOP-cleavable sequences within the conjugate and methods of treating patients with prodrugs of the invention.

Abstract: A new class of DNA vectors, each comprising two replication systems; a first origin of replication resulting in a low copy number and stable inheritance of the plasmid, and a second, high copy number, origin of replication at which replication is directly controllable such that, when host cells carrying the vector are propagated under a first set of conditions, replication takes mainly from the low copy number origin, and that when said cells are propagated under a second set of conditions, replication takes place also from the high copy number origin to produce a high yield of gene product. The controllable origin of replication may be under the control of a natural promoter of RNA transcription or a substitute promoter such as the PL promoter or lac promoter.