Stromal Antigen Targeting by a Humanised Monoclonal Antibody: An Early Phase II Trial of Sibrotuzumab in Patients with Metastatic Colorectal Cancer

Abstract

Background: A novel immunological approach to colon cancer therapy is the antibody targeting of the fibroblast activation protein (FAP), which is highly expressed by stroma cells of this tumour. Unconjugated sibrotuzumab (BIBH 1), which is a humanised version of the murine anti-FAP mAb F19, was investigated for its anti-tumour activity, safety and pharmacokinetics. Patients and Methods: Patients with metastatic colorectal cancer received weekly intravenous infusions of unconjugated sibrotuzumab at a dose of 100 mg over 12 scheduled weeks. The study was implemented as an open-label, uncontrolled, multicentre trial. Results: 25 patients were enrolled. Patients had one or more measurable lesions, predominantly liver lesions, at baseline. At least 8 repeated weekly infusions of sibrotuzumab in 17 evaluable patients did not result in complete or partial remission. Rather, ongoing tumour progression was noted in all patients except for 2 patients with stable disease. However, progressive disease was also observed post-study in these 2 patients who received 1 and 6 additional infusions, respectively, of sibrotuzumab. Sibrotuzumab exhibited 2-compartment pharmacokinetics with a dominant terminal phase and t1/2 ? = 5.3 ± 2.3 days. Adverse drug reactions (rigors/chills, nausea, flushing and one incidence of bronchospasm) were observed in 5 patients. Of the 24 patients given 2 or more infusions of sibrotuzumab, antibodies against sibrotuzumab were found in 3 patients (12.5%) after 4–12 infusions. Conclusions: Sibrotuzumab was well tolerated and safe. The minimal requirement for the continuation of this exploratory trial, of at least one complete or partial remission, or equivalently, of 4 patients with stable disease, was not met.

Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice

“…In antibody-based imaging studies, anti-FAP antibodies exhibited highly specific tumor targeting in patients (40). However, although a humanized anti-FAP antibody (mAb F19; sibrotuzumab) was well tolerated, it showed no efficacy in a phase II trial for metastatic colorectal cancer (39,53). It is important to note, however, that this particular antibody does not inhibit FAP activity or have direct cytotoxic activity.…”

Radioimmunotherapy of Fibroblast Activation Protein Positive Tumors by Rapidly Internalizing Antibodies

“…A humanized version of mAb F19 (sibrotuzumab), a first generation anti-FAP antibody, however, failed to show measurable therapeutic activity (24) in phase I/II clinical trials despite excellent tumor stroma targeting properties (25). In addition, 8 of 26 sibrotuzumab-treated patients developed human-anti-human antibodies (HAHA) with a change in pharmacokinetics and reduced tumor uptake in 4 of them.…”

Phase II trial of single agent Val-boroPro (talabostat) inhibiting fibroblast activation protein in patients with metastatic colorectal cancer

“…10 Given its ubiquitous expression in both primary and metastatic colorectal carcinomas, FAP has been targeted by monoclonal antibodies, 11 but these non-inhibitory antibodies did not show clinical activity. [11][12][13] We have previously shown that forced FAP overexpression by tumor cells in an animal model results in a significant enhancement in tumor growth. 14 This tumor growth potentiation is thought to be due to its proteolytic activity, as mutation of the catalytic serine residue abolishes FAP's proteolytic activity and subsequently eliminates the tumor growth advantage.…”