Abstract 4949: In vitro and in vivo investigation of the novel, first-in-class, Guanylyl Cyclase C (GCC) targeted 68Ga labeled heat stable peptide MLN6907 ([68Ga]MLN6907) for tumor imaging
Authors: Cvet Donna , Robertson Robert , Saylor Melissa , Terkelsen Jennifer , Yardibi Ozlem , Borland Maria , Salem Nicolas , Veiby Petter , Sells Todd , Carsillo Mary , Yang Johnny , Teng Shu-Wen , Hoppin John , Orcutt Kelly , Hesterman Jacob , Norenberg Jeffery , Anderson Tamara , Schulz Mike , Ruscowski Mary , Berridge Marc , Mather Steven , Bradley Daniel P. 
Published: May 2015

A novel, first-in-class, 68Ga labeled DOTA-para-bn-SCN-Ahx-STp(5-18) 2.2kDa peptide [MLN6907] ([68Ga]MLN6907) with high affinity to the guanalyl cyclase C (GCC) receptor has been developed to select cancer patients for treatment with GCC targeted therapies using PET/CT. GCC is sequestered exclusively in the gastrointestinal luminal compartment except under malignant transformation where it is then made accessible to intravenous agents.

Conventional patient selection strategies often rely on an analytical IHC or total protein based assessment of a tumor biopsy which can be limited to an archival tissue sample from a single region of a single lesion. Imaging may offer whole body, real time, multi-region and multi lesion assessment of target levels. In addition, functional parameters associated with receptor kinetics may also be explored in vivo.

68Ga has a high avidity for the common chelating moiety DOTA. Furthermore, its short radioactive half life (half-life, 68.3 minutes) matches well to a biological targeting moiety like a peptide with its rapid biological clearance and fast diffusion to target thus providing optimal tumour-to-normal tissue contrast.

In vitro: Cellular competitive binding studies confirmed high affinity of non-radiolabeled MLN6907 for its cognate receptor, GCC, with a KD of 3.2 nM. Upon ligand-recpetor binding, MLN6907 is internalized rapidly with a half-life of 56 min.

In vivo: Similar to other radiolabeled peptides, [68Ga]MLN6907 clears rapidly from blood (t1/2 = 26 min) through renal excretion as investigated in Long Evans rats and non-human primate studies. The radiation exposure from [68Ga]MLN6907 was highest in the kidney and bladder indicating that renal excretion was a primary route of elimination. Using OLINDA/EXM software, the effective dose was estimated to be 0.013 mSv/MBq in man. In tumor bearing C.B-17 SCID mice, both ex vivo and in vivo signal was measured in both human tumor cell lines and primary human tumor xenografts with varied GCC levels and compared to non tumor bearing tissues. [68Ga]MLN6907 total uptake (%I.D./g) varied across the different tumors investigated. Using the unlabeled precursor, no toxicity was observed in repeat dose rat and monkey studies. Using the rat as the more conservative species for dose estimation, it was calculated that a human equivalent dose of 282 μg would be safe. However, using a saturable effect PK/PD compartment model for mice and humans, we estimated a single human dose of less than 100μg would provide resolution of tumors with different GCC levels.

Collectively, biological, pharmacokinetic and safety data obtained with [68Ga]MLN6907 are consistent with an effective GCC PET imaging agent.

[68Ga]MLN6907 is being developed clinically as a single, i.v., microdose GCC PET imaging agent in a Phase 1 investigation in patients with surgically resectable metastatic colorectal carcinoma

Citation Format: Donna Cvet, Robert Robertson, Melissa Saylor, Jennifer Terkelsen, Ozlem Yardibi, Maria Borland, Nicolas Salem, Petter Veiby, Todd Sells, Mary Carsillo, Johnny Yang, Shu-Wen Teng, John Hoppin, Kelly Orcutt, Jacob Hesterman, Jeffery Norenberg, Tamara Anderson, Mike Schulz, Mary Ruscowski, Marc Berridge, Steven Mather, Daniel P. Bradley. In vitro and in vivo investigation of the novel, first-in-class, Guanylyl Cyclase C (GCC) targeted 68Ga labeled heat stable peptide MLN6907 ([68Ga]MLN6907) for tumor imaging. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4949. doi:10.1158/1538-7445.AM2014-4949