CD22 is a type I transmembrane sialoglycoprotein, which expression is restricted to the B-cell lineage. CD22 is also found highly expressed on most malignant mature B cells, including follicular non-Hodgkin lymphoma (NHL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL).
The differential and favorable expression profile of CD22 in normal and tumor tissues, together with its rapid internalization upon binding with a ligand or antibody, make CD22 an attractive target for an antibody drug conjugate (ADC) mediated treatment of B-cell malignancies. hLL2-PBD is an ADC composed of the humanized monoclonal antibody epratuzumab (hLL2) against human CD22 stochastically conjugated via a valine-alanine cleavable, maleimide linker to a PBD dimer. PBD dimers represent a novel class of payloads, which bind in the DNA minor groove and form highly cytotoxic DNA interstrand cross-links. The average drug to antibody ratio (DAR) of hLL2-PBD is 2.
In vitro, hLL2-PBD showed potent and specific cytotoxicity, as assessed by the MTS assay, in the CD22-positive human Burkitt's lymphoma-derived cell lines Ramos and Daudi and the human diffuse large B-cell lymphoma-derived cell line WSU-DLCL2.
In vivo, hLL2-PBD demonstrated potent anti-tumor efficacy in subcutaneously (s.c.) implanted Daudi and Ramos xenograft models. In the Daudi model, hLL2-PBD, administered as a single dose at either 0.1 or 0.3 mg/kg, achieved dose-dependent anti-tumor activity, resulting in significant increase in survival. At 0.3 mg/kg, hLL2-PBD induced complete tumor regression in all treated animals. In the Ramos xenograft model, a single dose of 1 mg/kg of hLL2-PBD achieved strong tumor regression. Moreover, hLL2-PBD achieved a superior anti-tumor activity compared to Hu10F4-vcMMAE, a CD22-targeting ADC with the auristatin payload vcMMAE and a DAR of 4 (Genentech Inc.), when tested at 1 mg/kg, single dose. Pharmacokinetic (PK) analysis of hLL2-PBD in CB.17 SCID mice showed a favorable PK profile, with a half-life of approximately 12 days.
In conclusion, these data demonstrate the potent in vitro and in vivo anti-tumor activity of hLL2-PBD against CD22-positive hematological tumors and warrant further development of this ADC into the clinic.
Citation Format: Francesca Zammarchi, David Williams, Karin Havenith, Francois D'Hooge, Philip W. Howard, John A. Hartley, Patrick van Berkel. Preclinical activity of hLL2-PBD, a novel anti-CD22 antibody-pyrrolobenzodiazepine (PBD) conjugate in models of non-Hodgkin lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 637. doi:10.1158/1538-7445.AM2015-637