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Drug Candidate: scFVMEL-TNF-alpha (single-chain immunotoxin)

Indications: Melanoma and other gp240+ tumors
Stage: Advanced Pre-clinical
Overview: scFvMel/TNF-alpha is being developed for the treatment of metastatic melanoma and other gp240+ (High Molecular Weight Melanoma-Associated Antigen-positive) tumors.

ScFvMEL/TNF-alpha is an unglycosylated, low molecular weight (45 kDa) recombinant fusion protein consisting of a single chain antibody fragment (scFvMEL) that targets a high percentage of melanomas, genetically fused to the human cytokine tumor necrosis factor-alpha (TNF-alpha). TNF-alpha itself naturally forms into a compact trimer in solution. Analysis of ScFvMEL/TNF also demonstrates that the fusion construct exists in solution as a trimer of ~135 kDa. ScFvMEL/TNF-alpha is manufactured in E. coli.

ScFvMEL consists of a small flexible linker engineered between the variable domains of the heavy and light chains of the antibody ZME-018 and attached via a tether (G4S) to TNF-alpha. This molecule has the binding properties of the original anti-melanoma antibody and contains biologically active cytokine.

The progenitor ZME-018 antibody binds to a surface glycoprotein (gp240) found on over 80% of human melanoma cell lines and biopsy specimens. Studies have demonstrated that this antigen may be expressed on other tumor types, as well.

Pre-clinical studies on various human melanoma cell lines and melanoma (A-375) tumor bearing nude mice strongly indicate that scFvMEL/TNF-alpha has potent cytotoxic activity both in vitro and in vivo and is an excellent candidate for clinical development. ScFvMEL/TNF-alpha also has a sister molecule, ScFvMEL/rGel, which uses recombinant gelonin instead of human TNF-alpha as its payload.

Developmental Status

Targa has completed most preclinical development on scFvMEL/TNF-alpha including numerous efficacy and toxicity animal studies. Targa plans to begin manufacturing this compound before the end of 2006 in preparation for Phase I clinical trials at The University of Texas M.D. Anderson Cancer Center (MDACC).

Preclinical milestones completed:

Pre-IND package completed and submitted to FDA.
Pre-IND guidance call held with FDA; agreement reached with the agency on clinical and pre-clinical requirements for Phase I initiation.
Additional work required by FDA (<$100K) initiated and ~67% completed.
Phase I clinical protocol Approved by M.D. Anderson Cancer Center (MDACC) Institutional Review Board (IRB).
MDACC Clinical Principal Investigator (PI) and team recruited and ready to proceed.
Contract Manufacturing Organization (CMO) selected and inspected in detail.
Manufacturing Process Instructions (MPI’s) nearing completion.

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