Anti-CD22-MCC-DM1: an antibody-drug conjugate with a stable linker for the treatment of non-Hodgkin's lymphoma

Abstract

Antibody-drug conjugates (ADCs) are potent cytotoxic drugs linked to antibodies through chemical linkers, and allow specific targeting of drugs to neoplastic cells. The expression of CD22 is limited to B-cells, and we show that CD22 is expressed on the vast majority of non-Hodgkin's lymphomas (NHLs). An ideal target for an ADC for the treatment of NHL would have limited expression outside the B-cell compartment and be highly effective against NHL. We generated an ADC consisting of a humanized anti-CD22 antibody conjugated to the anti-mitotic agent maytansine with a stable linker (anti-CD22-MCC-DM1). Anti-CD22-MCC-DM1 was broadly effective in in vitro killing assays on NHL B-cell lines. We did not find a strong correlation between in vitro potency and CD22 surface expression, internalization of ADC or sensitivity to free drug. We show that anti-CD22-MCC-DM1 was capable of inducing complete tumor regression in NHL xenograft mouse models. Further, anti-CD22-MCC-DM1 was well tolerated in cynomolgus monkeys and substantially decreased circulating B-cells as well as follicle size and germinal center formation in lymphoid organs. These results suggest that anti-CD22-MCC-DM1 has an efficacy, safety and pharmacodynamic profile that support its use as a treatment for NHL.

DCDT2980S, an Anti-CD22-Monomethyl Auristatin E Antibody–Drug Conjugate, Is a Potential Treatment for Non-Hodgkin Lymphoma

“…The antibody anti-CD22 10F4 has been previously identified as an antibody to CD22 that is particularly effective as an ADC compared with other anti-CD22 antibodies when tested in xenograft models (6). The humanized form of 10F4 (MCDT2219A; Hu10F4; ref.…”

“…The humanized form of 10F4 (MCDT2219A; Hu10F4; ref. 6) was conjugated to MC-vc-PAB-MMAE though the interchain disulfide cysteines (Fig. 1A) as previously described (14).…”

“…The antibody for DCDT2980S (MCDT2219A, Hu10F4) was generated and humanized as previously described (6). The antibody was conjugated as previously described (14).…”

“…Previously we identified CD22 and CD79 as superior targets for antibody-drug conjugate (ADC), potent cytotoxic drugs linked to antibodies via chemical linkers, therapy for the treatment of NHL (5)(6)(7). CD22 is a 130 kDa type I transmembrane glycoprotein, normally expressed on B-lineage cells from the pre-B-cell stage, and to being fully expressed on all subtypes of mature Bcell and downregulated from the surface of plasma cell.…”

Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy

“…15,16 Numerous studies indicated maytansinoid DM1 (derivative of maytansine), a highly potent microtubule polymerization inhibitor, was an ideal payload for developing ADC. [17][18][19][20] Furthermore, antibody-DM1 conjugates have shown promising results in preclinical and clinical evaluations. 21 As a member of the EGFR family, HER2 is a clinically validated ADC target.…”