Selective Apoptotic Killing of Malignant Hemopoietic Cells by Antibody-Targeted Delivery of an Amphipathic Peptide

Abstract

The A-helical amphipathic peptide D-(KLAKLAK) 2 is toxic to eukaryotic cells if internalized by a suitable targeting mechanism. We have targeted this peptide to malignant hemopoietic cells via conjugation to monoclonal antibodies, which recognize lineage-specific cell surface molecules. An anti-CD19/peptide conjugate efficiently killed 3/3 B lymphoid lines. However, an anti-CD33/peptide conjugate was cytotoxic to only one of three CD33-positive myeloid leukemia lines. The IC 50 towards susceptible lines were in the low nanomolar range. Conjugates were highly selective and did not kill cells that did not express the appropriate cell surface cognate of the antibody moiety. Anti-CD19/ peptide conjugates efficiently killed cells from patients with chronic lymphocytic leukemia but anti-CD33/peptide reagents were less effective against fresh acute myeloid leukemia cells. We therefore suggest that amphipathic peptides may be of value as targeted therapeutic agents for the treatment of a subset of hematologic malignancies.

Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma

“…We made use of this unique ability of CGKRK to reach the mitochondria by using the amphiphilic proapoptotic peptide D [KLAKLAK] 2 as the payload. D [KLAKLAK] 2 has been shown to act on mitochondria, the target of CGKRK (10), and several reports have described the antitumor activities of D [KLAKLAK] 2 (and some other peptides with similar activities), when selectively delivered to a target tissue (11)(12)(13)(14)(15)(27)(28)(29). The main limitation of these treatments has been that the D [KLA-KLAK] 2 peptide is highly toxic at the doses required for tumor treatment even with specific targeting.…”

Antitumor activity of a membrane lytic peptide cyclized with a linker sensitive to membrane type 1-matrix metalloproteinase

“…D-amino acid replacement is the most common sequence-modifying method. Conjugating peptides with targeting ligands such as antibodies was also reported (18). Another strategy is via activation by tumor-associated enzymes or lower pH in the pathologic microenvironment of tumor tissues.…”

“…However, most membrane lytic peptides do not differentiate normal cells and cancer cells. Research has been conducted to render peptides more selective and some success has been achieved (3,14,15,17,18,40). Structure-function investigations enable the rational design of peptides that preferentially kill microbes (3) or cancer cells (17).…”

Identification and Validation of Targets for Cancer Immunotherapy: From the Bench-to-Bedside

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