Pharmacokinetics, immunogenicity and safety of bivatuzumab mertansine, a novel CD44v6-targeting immunoconjugate, in patients with squamous cell carcinoma of the head and neck.

The prodrug bivatuzumab mertansine (BIWI 1) is a novel CD44v6-targeting humanized monoclonal antibody coupled to the toxin mertansine. In a phase I dose escalation trial 31 patients with squamous cell carcinomas of the head and neck were treated with doses of 25-325 mg/m2 as a 30-min infusion. Thirteen patients received a second infusion after 3 weeks. Serial serum samples were collected to determine the pharmacokinetic parameters of the prodrug BIWI 1 and of deconjugated BIWI 1 as well as the occurrence of anti-BIWI 1 antibodies. The maximum tolerated dose was reached at 300 mg/m2 attributable to skin toxicity. No immune response was observed in any patient. For BIWI 1 and deconjugated BIWI 1, clearance values were low and distribution was limited resulting in half-lives of approximately 3-3.5 days and approximately 6-7 days, respectively, for single and repeated dosing after three weeks. Overall, interindividual variability of the pharmacokinetic parameters was low. In general, the pharmacokinetics of both compounds after single and repeated dosing was comparable across the entire dose range and no significant accumulation took place. Over the dose range investigated, a dose proportional increase in the exposure of BIWI 1 and deconjugated BIWI 1 was observed. Dose individualization according to body size (weight or body surface area) was found to be appropriate and is recommended for the novel immunoconjugate.

Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma.

CD44v6 is a tumor associated antigen abundantly expressed in head and neck squamous cell carcinomas (HNSCC) and in normal squamous epithelium. The immunoconjugate bivatuzumab mertansine (BIWI 1) consists of a highly potent antimicrotubule agent coupled to a monoclonal antibody against CD44v6. The maximum tolerated dose (MTD), safety and efficacy of BIWI 1 administered IV in patients with HNSCC has not been determined. In a clinical phase I trial, adult patients with recurrent or metastatic HNSCC were treated intravenously with BIWI 1. Starting with 25mg/m(2), the dose was escalated in steps of 25mg/m(2) until dose limiting toxicity was observed. Six women and 25 men were included. The MTD was 300 mg/m(2). Twelve patients were treated with at least the MTD. The principal toxic effects were maculopapular rashes, focal blister formation and skin exfoliation. Three patients had partial responses at doses of 200, 275 and 325 mg/m(2). The concept that bivatuzumab can direct mertansine activity to CD44v6 expressing tumors was confirmed. Although CD44v6 was abundantly expressed in all tumors, the response to BIWI 1 was variable. Binding to CD44v6 on skin keratinocytes mediated serious skin toxicity with a fatal outcome in a parallel trial, which led to the termination of the development program of bivatuzumab mertansine and the present study.

Adoptive therapy of head and neck squamous cell carcinoma with antibody coated immune cells: a pilot clinical trial.

BACKGROUND: Catumaxomab is an antibody that binds with one arm epithelial cell adhesion molecule (EpCAM) positive tumors and with the other arm CD3+ T cells. Intravenous application of therapeutic antibodies may result in intravascular cytokine release. AIM: In this pilot trial we assessed whether cytokine release can be controlled by ex vivo cell opsonization and cytokine wash-out before administration of catumaxomab, preserving its anti-cancer activity. In addition, preliminary data on safety of and clinical response to catumaxomab coated autologous immune cells were acquired. METHODS: Peripheral blood mononuclear cells (PBMNC) of four patients with recurrent head and neck carcinoma were collected by leukapheresis, incubated ex vivo with catumaxomab for 24 h and cleared from released cytokines. Each patient received an escalated number of antibody-coated PBMNC equivalent to 1 x 10(4), 1 x 10(5), 1 x 10(6) and 1 x 10(7) CD3(+) cells/kgBW intravenously at bi-weekly intervals. RESULTS: After opsonization, PBMNC released substantial amounts of interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) in vitro, which were removed before administration. Catumaxomab up-regulated CD25, CD69, and CD83 on PBMNC, and catumaxomab loaded PBMNC released IFNgamma and granzyme B when coincubated with EpCAM(+) BHY cells, suggesting cell activation and target directed biological activity. During the study period, one patient died of aspiration pneumonia and one patient needed a tracheotomy. Treatment related adverse events (AE) occurred at the highest cell dose in two patients, whereas 1 x 10(6) loaded CD3(+) cells/kgBW were well tolerated by all patients. One patient showed stable disease for 6 months and one patient is in complete remission for 27 months. CONCLUSION: Ex vivo opsonization of PBMNC with catumaxomab provided biologically active, tumor targeting cells. Extracorporeal PBMNC coating may be an option to control intravascular cytokine release induced by therapeutic antibodies.