Generation and optimization of a chimeric antigen receptor against CD22: a new immunotherapeutic agent for treating B-lineage leukemia and lymphoma

Wednesday, October 26, 2011 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center	NCI	CLIN/CULT/AGING/DISPREV-7

Authors

• W Haso
• I Pastan
• R Morgan
• C Mackall
• R Orentas

Abstract

CD22 is expressed on a number of hematologic malignancies. A recombinant immunotoxin composed of an anti-CD22 Fv fused to a 38 kDa fragment of Pseudomonas exotoxin A (Moxetumomab pasudodtox, HA22) is currently being evaluated in the treatment of B cell malignancies. We used the Fv sequence to construct a series of chimeric antigen receptors (CARs) to determine the optimal affinity, domain structure, and signaling required for optimal anti-leukemic activity. The original anti-CD22 binding domain, BL22, or a high-affinity domain, HA22, were fused to transmembrane and signaling sequences derived from the TCR zeta-chain, CD28, and CD137. In some constructs we extended the binding domain away from the membrane using constant domains from IgG (CH2CH3). Retroviral gene vectors were used to transduce activated primary T cells with CAR constructs. We found: HA22 Fv, 2 as opposed to 3 signaling motifs, and non-CH2CH3 containing CARs were superior in CTL assays, indicating that Fv affinity, signaling, and 3-D structure all impact anti-leukemic effectiveness. Finally, direct comparison to CD19-specific CAR showed an equivalent or superior killing activity in 2 out of 3 ALL lines tested. Our results indicate that CD22-CAR should be developed for the immunotherapy of CD22+ leukemias.

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