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Drug Candidate: BreMel/rGel (scFvMel/rGel) (single-chain immunotoxin)

Indications: Breast Cancer and Melanoma
Stage: Pre-clinical
Overview: BreMel/rGel is currently being preclinically developed for the treatment and prophylaxis of metastatic melanoma and a molecularly-defined subset of breast cancers.

BreMel/rGel (aka scFvMel/rGel) is an unglycosylated, low molecular weight (46 kDa) recombinant fusion protein. BreMel/rGel consists of a single chain antibody fragment (scFv) genetically fused to the toxin payload rGel (recombinant gelonin). It can be readily manufactured inexpensively and efficiently in E. coli fermenters.

The construct uses a small flexible linker between the variable domains of the heavy and light chains of the antibody ZME-018 attached via a tether (G4S) to the recombinant gelonin. This molecule has the binding properties of the original anti-melanoma antibody and contains biologically active toxin.

The original antibody binds to a surface glycoprotein (gp240) found on over 80% of human melanoma cell lines and biopsy specimens. While most melanomas are currently treated surgically, metastatic disease with a highly negative prognosis remains a significant risk for such patients. New agents for both the prophylaxis and treatment of metastatic melanoma are currently needed. Recent studies also have demonstrated that this antigen is expressed on 67% (44/66) of lobular breast carcinomas studied. Lobular breast carcinomas account for about 15% of all breast cancers and appear to be an immunologically distinct subclass from HER2+ breast cancers.

Pre-clinical studies on A-375 Melanoma cell lines and A-375 tumor bearing nude mice strongly indicate that BreMel/rGel has potent cytotoxic activity both in vitro and in vivo and is an excellent candidate for clinical development. BreMel/rGel also has a sister molecule, BreMel/TNF-alpha (aka scFvMel/TNF), which uses human TNF-alpha instead of recombinant gelonin as its payload. Although not as far developed clinically, BreMel/TNF-alpha is also showing very good activity in animal models.

Targa has completed most pre-clinical development on BreMel/rGel and expects to file an IND for this compound within 12 months.

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