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S.W. Hicks et al.
DLBCL subcutaneous and systemic tumor models. The improved activity of huB4-DGN462 compared to SAR3419 can be attributed to the increased potency of the linker/payload combination of sulfo-SPDB-DGN462 com- pared to SPDB-DM4.
HuB4-DGN462 was highly active in multiple cell lines derived from B-cell lymphomas. The antitumor activity was not affected by the lymphoma histology or DLBCL subtype or TP53, BCL2 or MYC gene status. Despite specificity for CD19, similar to other ADC, the anti-lym- phoma activity of huB4-DGN462 did not correlate with the absolute expression level of CD19,30,31 but rather the sensitivity of the cell line to the free payload. The impres- sive potency of huB4-DGN462 observed is likely to be due to the fact that low target expression was sufficient to deliver a cytotoxic concentration of the novel linker/pay- load combination. Given the broad expression profile of CD19 in B-cell malignancies, CD19 is an attractive target for cancer therapy. In particular, CD19-targeting immunotherapies have seen recent successes with the US Food and Drug Administration (FDA) approvals of the bis- pecific T-cell engaging antibody blinatumomab (Blincyto)32-34 and the FDA approvals of two chimeric anti- gen receptors (CAR) T-cell therapies targeting CD19, tis- agenlecleucel (Kymriah)35 and axicabtagene cilolecucel
(Yescarta).36 Despite the success of CD19-targeting immunotherapies, there still remains the need for more effective therapies, particularly in patients with relapsed/refractory lymphomas such as DLBCL. The clin- ical activity of CD19-targeting ADC following other anti- CD19 directed therapeutic modalities32-39 will have to be determined. However, unlike immunotherapies that stim- ulate the patient’s immune systems to fight cancer, ADC like huB4-DGN462 kill tumor cells by delivering a cyto- toxic payload directly to tumor cells. Given the distinct difference in mechanism of action of ADC to that of immunotherapies, patients have the potential to benefit from both types of therapies.
This work demonstrates that huB4-DGN462 has superi- or preclinical antitumor activity compared to clinically- validated SAR3419. Each of the individual components of huB4-DGN462 (antibody, linker and payload) have passed early clinical evaluation13,25 making huB4-DGN462 an attractive candidate for clinical investigation with the potential to extend the lives of patients with B-cell malig- nancies.
Funding
Partially supported by institutional research funds from ImmunoGen and the Gelu Foundation (to FB).
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