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Drug Candidate: VEGF/rGel (vascular disruptive agent, fusion toxin)
VEGF/rGel-Op (ophthalmic)

Indications: Metastases, Solid Tumors, Diabetic Retinopathy, and Age-Related Macular Degeneration
Stage: Advanced Pre-clinical
Overview: VEGF/rGel (VEGF121/rGel) is a vascular disruptive agent being developed for the treatment of bone metastases, multiple solid tumors and ocular diseases including wet age-related macular degeneration (AMD) and diabetic retinopathy.

VEGF/rGel is a fusion protein which targets and ablates osteoclast precursor macrophage cells through a VEGFR1-mediated mechanism. It also targets and ablates solid tumor microvasculature through a VEGFR2 (KDR)-mediated mechanism, without harming normal vasculature. This dual activity from a single compound may provide a medical advantage in treating certain tumors such as breast cancer.

VEGF/rGel is comprised of full-length human Vascular Endothelial Growth Factor (VEGF121), which retains full functionality for receptor interaction, tethered via a flexible G4S linker to toxin payload recombinant Gelonin (rGel). It can be readily manufactured inexpensively and efficiently in E. coli fermenters. Recombinant gelonin (rGel) is a 30-kDa single chain protein that inactivates the 28S ribosomal subunit via a well-defined molecular mechanism.

Preclinical Development:

Animal studies using VEGF/rGel have been completed for the following tumors and ocular disorders:

Metastases

1) skeletal metastases from prostate tumors,
2) lung metastases from breast tumors,

Solid Tumors

1) orthotopic bladder,
2) orthotopic pancreatic,
3) orthotopic breast,
4) subcutaneous prostate,
5) orthotopic melanoma,

Ocular Disease

1) diabetic retinopathy (DR), and
2) age-related macular degeneration (AMD).

VEGF/rGel showed potent specific cytoxicity in all of these models and is an excellent candidate for clinical development.

VEGF/rGel also has a sister molecule, GrB/VEGF, which uses Granzyme B instead of rGEL as its payload. Although not as well-developed pre-clinically, GrB/VEGF also demonstrated excellent cytotoxic effects in vitro. The cytotoxic properties of the GrB/VEGF molecule are mediated through a unique mechanism of action.

Developmental Status

Targa has completed most preclinical development on VEGF/rGel including numerous 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: reached agreement on pre-clinical and clinical issues.
Additional work required by FDA (<$100K) initiated and ~50% completed.
Phase I clinical protocol approved by MDACC Institutional Review Board (IRB).
MDACC Clinical Principal Investigator and team recruited and ready to proceed.
Contract Manufacturing Organization (CMO) selected and detailed inspection completed.
Manufacturing Process Instructions (MPI’s) completed and ready for transfer to CMO.

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