Andrew M. Scott
Ludwig Institute for Cancer Research, Austin & Repatriation Medical Centre, Melbourne, Australia

Tumor Stromal and Cell-Surface Targeting with Novel Recombinant Antibodies

Our research program has focused on developing recombinant antibodies to selected antigens and receptors on stromal and cellular compartments of tumors, and exploiting this targeting approach for directed tumor cell killing in-vivo.

We have explored the targeting of the stromal compartment of tumors via the cell surface molecule fibroblast activation protein (FAP), expressed on activated fibroblasts in the stroma of most epithelial cancers. In a human skin/SCID mouse model we have demonstrated the selective targeting of xenograft stroma with a recombinant antibody to human FAP. In collaboration with Boehringer Ingelheim Pharmaceuticals Inc. we have evaluated a CDR-grafted humanized antibody directed against human FAP (BIBH 1) in Phase I trials in patients with FAP-positive cancers. In the first trial BIBH 1 was administered weekly for 12 weeks, at dose levels of 5, 10, 25 or 50 mg/m2, and a total of 26 patients were entered into the trial. One episode of DLT was observed, and MTD was therefore not reached. Gamma camera images of 131I-BIBH 1 demonstrated no normal organ uptake of BIBH 1, with tumor uptake evident within 24-48 hours post infusion. Pharmacokinetic analysis demonstrated a similar mean terminal T½ of 1.6-2.7 days at the 5, 10 and 25 mg/m2 dose levels, and a terminal T½ of 4.9 days at the 50mg/m2 dose level. Further clinical trials are underway to exploit the selective stromal targeting of this antibody, including the delivery of
b-emitting isotopes for tumor stromal and vascular ablation.

In collaboration with Kyowa Hakko Kogyo Co. Ltd. we have developed a chimeric monoclonal antibody KM871, which targets the ganglioside antigen GD3 expressed on melanoma cells. We have completed a Phase I trial in patients with metastatic melanoma, with 17 patients entered into one of five dose levels (1, 5, 10, 20 and 40 mg/m2). Patients received 3 infusions of KM871 at 2-week intervals, with the first infusion of KM871 trace labelled with 111In. There was no DLT observed during the trial, and MTD was therefore not reached. Three patients (at the 1, 5 and 40mg/m2 dose levels) developed pain and/or erythema at tumor sites consistent with an inflammatory response. Importantly, no normal tissue uptake of 111In-KM871 was observed. 111In-KM871 uptake in tumor biopsies ranged from 0.001-0.026 %ID/gm, and tumor : normal tissue ratios up to 15:1. Pharmacokinetic analysis revealed a mean terminal T½ of 7.68 + 2.94 days for 111In-KM871, and there was no serological evidence of HACA in any patient following KM871 infusions. This study is the first to demonstrate the biodistribution and specific targeting of an anti-GD3 antibody to metastatic melanoma in-vivo, and further trials are planned.

The targeting of the Ley antigen and the truncated EGFR receptor, expressed on epithelial tumors, is also being evaluated in our laboratory, and extended to clinical trials. The selective targeting of tumors with recombinant antibodies and evaluation of novel cell killing mechanisms shows great promise for cancer therapy.