A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma

Abstract

AFM13 is a bispecific, tetravalent chimeric antibody construct (TandAb) designed for the treatment of CD30-expressing malignancies. AFM13 recruits natural killer (NK) cells via binding to CD16A as immune effector cells. In this phase 1 dose-escalation study, 28 patients with heavily pretreated relapsed or refractory Hodgkin lymphoma received AFM13 at doses of 0.01 to 7 mg/kg body weight. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, antitumor activity, and pharmacodynamics. Adverse events were generally mild to moderate. The maximum tolerated dose was not reached. Pharmacokinetics assessment revealed a half-life of up to 19 hours. Three of 26 evaluable patients achieved partial remission (11.5%) and 13 patients achieved stable disease (50%), with an overall disease control rate of 61.5%. AFM13 was also active in brentuximab vedotin-refractory patients. In 13 patients who received doses of ≥1.5 mg/kg AFM13, the overall response rate was 23% and the disease control rate was 77%. AFM13 treatment resulted in a significant NK-cell activation and a decrease of soluble CD30 in peripheral blood. In conclusion, AFM13 represents a well-tolerated, safe, and active targeted immunotherapy of Hodgkin lymphoma. A phase 2 study is currently planned to optimize the dosing schedule in order to further improve the therapeutic efficacy. This phase 1 study was registered at www.clinicaltrials.gov as #NCT01221571.

© 2015 by The American Society of Hematology.

Figures

Figure 1

Folding pathway of AFM13. The fully functional TandAb antibody is formed by homodimerization of a single polypeptide in a head-to-tail fashion through noncovalent interactions of the immunoglobulin heavy (VH) and light (VL) variable chains of the constituting domains. The human anti-CD16A (FcγRIIIA) antibody domain (VHA/VLA) with specificity for the A isoform of FcγRIII on NK cells and macrophages was isolated from Affimed’s human antibody library. The murine anti-CD30 variable domain (VHB/VLB) was derived from hybridoma HRS-3.

Figure 2

Mean serum concentrations of AFM13 following a single IV infusion of increasing doses of AFM13.

Figure 3

Change in the sum of the product of diameters, measured by computed tomography. (A) Efficacy population (n = 26). (B) Patients refractory to brentuximab vedotin as the most recent treatment prior to AFM13 (n = 7). (C) Patients treated with AFM doses ≥1.5 mg/kg body weight (n = 13).

Figure 4

Number of activated NK cells (CD69+) relative to total number of NK cells (CD16+ or CD56+; CD3−). Change from baseline (=100%) for all patients receiving doses ≥0.15 mg/kg AFM13 (n = 22).