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In this study, the HB22.7 anti-CD22 mAb, was used for specific, targeted delivery of the potent anti-cancer agent, monomethyl auristatin E (MMAE) to non-Hodgkin lymphoma (NHL). MMAE was covalently coupled to HB22.7 through a valine-citrulline peptide linker (vc). Maleimide-functionalized vcMMAE (mal-vcMMAE) was reacted with thiols of the partially reduced mAb. Approximately 4 molecules of MMAE were conjugated to HB22.7 as determined by residual thiol measurement and hydrophobic interaction chromatography-HPLC (HIC-HPLC). HB22.7-vcMMAE antibody drug conjugate (ADC) retained its binding to Ramos NHL cells and also exhibited potent and specific in vitro cytotoxicity on a panel of B cell NHL cell lines with IC(50)s of 20 - 284 ng/ml. HB22.7-vcMMAE also showed potent efficacy in vivo against established NHL xenografts using the DoHH2 and Granta 519 cell lines. One dose of the ADC induced complete and persistent response in all DoHH2 xenografts and 90% of Granta xenografts. Minimal toxicity was observed. In summary, HB22.7-vcMMAE is an effective ADC that should be evaluated for clinical translation.

Most patients with lung cancer still die from their disease, necessitating additional options to improve treatment. Here, we provide evidence for targeting CD22, a cell adhesion protein known to influence B-cell survival that we found is also widely expressed in lung cancer cells. In characterizing the antitumor activity of an established anti-CD22 monoclonal antibody (mAb), HB22.7, we showed CD22 expression by multiple approaches in various lung cancer subtypes, including 7 of 8 cell lines and a panel of primary patient specimens. HB22.7 displayed in vitro and in vivo cytotoxicity against CD22-positive human lung cancer cells and tumor xenografts. In a model of metastatic lung cancer, HB22.7 inhibited the development of pulmonary metastasis and extended overall survival. The finding that CD22 is expressed on lung cancer cells is significant in revealing a heretofore unknown mechanism of tumorigenesis and metastasis. Our work suggests that anti-CD22 mAbs may be useful for targeted therapy of lung cancer, a malignancy that has few tumor-specific targets. Cancer Res; 72(21); 5556–65. ©2012 AACR.

Vincristine (VCR) is a potent anti-cancer drug but its clinical efficacy is dose-limited by severe neurotoxicity. Prophylactic and palliative treatment of VCR-induced toxicity have been explored without significant findings. The field of drug delivery may provide an opportunity to increase the therapeutic index of VCR by delivering the drug specifically to tumor sites while sparing normal tissue. We have recently developed a telodendrimer (PEG5k-Cys4-L8-CA8) capable of forming disulfide cross-linked micelles which can encapsulate a variety of chemotherapeutics. In the present study, we encapsulate VCR into these micelles (DCM-VCR) and use them to treat lymphoma bearing mice. DCM-VCR particles have a size of 16 nm which is ideal for tumor accumulation via the enhanced permeability and retention (EPR) effect. Compared to our first-generation non-cross-linked micelles, DCM-VCR demonstrated greater stability and slower drug release in physiological conditions. In addition, DCM-VCR exhibited an MTD of 3.5 mg/kg while the MTD for conventional VCR was only 1.5 mg/kg. Using a NIRF dye, we showed that DCM-VCR accumulated at the tumor site starting 1 h after injection and persisted up to 72 h in lymphoma bearing mice. In an in vivo efficacy study, high dose (2.5 mg/kg) DCM-VCR exhibited the greatest reduction in tumor volume. High dose DCM-VCR was well tolerated and did not cause additional toxicity as measured by body weight, complete blood count, serum chemistry and histological analyses of the sciatic nerve. Mice treated with equivalent concentrations (1 mg/kg) of conventional VCR and DCM-VCR controlled tumor growth equally, however, in combination with on-demand addition of the reducing agent, N-acetylcysteine, DCM-VCR exhibited a superior anti-tumor effect compared to conventional VCR.

Antibody drug conjugates (ADCs) can deliver potent drugs to cancer cells by employing the specificity of monoclonal antibodies (mAbs). ADCs have demonstrated significant anticancer activity and, in 2011, brentuximab vedotin has been approved by the FDA for the treatment of Hodgkin#39;s and anaplastic large cell lymphomas. CD22 is an ideal target for ADC against B-cell malignancies because of its lineage-specific expression and rapid internalization upon antibody binding. In this study, we evaluated the anti-CD22 mAb HB22.7 as a vehicle for the targeted delivery of the potent toxin saporin (SAP). In vitro, HB22.7-SAP was cytotoxic against a panel of non-Hodgkin#39;s lymphoma (NHL) cell lines representing the most common types of the disease. Moreover, in a xenograft model of NHL, HB22.7-SAP significantly inhibited the growth of established lesions and completely prevented tumor development when treatment was initiated within 24 h from tumor-cell inoculation. HB22.7-SAP had no significant in vivo toxicity. In conclusion, HB22.7 constitutes a potential platform for CD22-targeted ADCs.