Regression of Cutaneous Tumor Lesions in Patients Intratumorally Injected with a Recombinant Single-chain Antibody-toxin Targeted to ErbB2/HER2

Abstract

ScFv(FRP5)-ETA is a recombinant single-chain antibody-toxin with binding specificity for ErbB2/HER2. Previously potent antitumoral activity of the molecule against ErbB2 overexpressing tumor cells was demonstrated in vitro and in animal models. Here we report on the first application of scFv(FRP5)-ETA in human cancer patients summarizing case reports collected in four different clinical centers. Eleven patients suffering from metastatic breast and colorectal cancers and from malignant melanoma were treated on a compassionate-use basis by intratumoral injection of scFv(FRP5)-ETA into cutaneous lesions once daily for 7-10 days. Total daily doses ranged from 60 to 900 microg, and total doses per treatment cycle ranged from 0.6 to 6.0 mg. Treatment caused injected tumors to shrink in six of the 10 cases evaluated (60%). Complete regression of injected tumor nodules was accomplished in four patients (40%) and partial reduction in tumor size in another two patients (20%). Adverse reactions were restricted to local symptoms such as pain and inflammation at injection sites which were fully reversible. Only in one patient treated at the highest daily doses systemic liver toxicity of grade 2 was observed and treatment was discontinued on day 7. No hematologic, renal, and/or cardiovascular toxicities were noted. Our results demonstrate that local therapy with scFv(FRP5)-ETA can be effective against ErbB2 expressing tumors justifying further clinical development of this reagent.

Antibody-Based Immunotoxins for the Treatment of Cancer

“…The treatment was given by intra-tumoral injection. Out of 11 patients, 4 showed complete remission and 3 showed partial remissions [56]. Another phase I trial was reported in 2005.…”

Targeted Delivery of the ErbB2/HER2 Tumor Antigen to Professional APCs Results in Effective Antitumor Immunity

“…Gene amplification and ErbB2 overexpression have been observed in many human tumors, including breast and ovarian cancers, nonsmall cell lung cancers, and cancers of the head and neck, and have been linked with cancer development and progression (3)(4)(5). With humanized mAb Herceptin, an ErbB2-specific reagent is in clinical use for immunotherapy of breast cancer (6), and alternative Abbased therapeutics are under development (7,8).…”

Single-Chain Antibody-Based Immunotoxins Targeting Her2/neu: Design Optimization and Impact of Affinity on Antitumor Efficacy and Off-Target Toxicity

“…Anti-Her2/neu immunotoxins containing PE have shown potent antitumor activity in animal models (23,33) but resulted in unexpected hepatotoxicity in all patients likely due to the normal presence of Her2/neu on hepatocytes (34,35). Studies by Onda and colleagues found that overall positive charge on anti-Tac(Fv) PE38 immunotoxin contributed to nonspecific binding to liver cells and resulted in dose-limiting liver toxicity (36,37).…”