Promiximab-duocarmycin, a new CD56 antibody-drug conjugates, is highly efficacious in small cell lung cancer xenograft models

Abstract

Small cell lung cancer (SCLC) is of a highly invasive and metastatic lung cancer subtype and there had not been effective targeted therapies. CD56, a cell surface marker highly expressed on most SCLC, is a promising therapeutic target for treatment of this aggressive cancer. In this study, we generated a novel anti-CD56 antibody named promiximab, characterized by high affinity, internalization and tumor specificity. Then, the promiximab was conjugated with a potent DNA alkylating agent duocarmycin via reduced interchain disulfides to yield the promiximab-Duocarmycin (promiximab-DUBA) conjugates. Mass spectrometry analysis showed promiximab-DUBA had an average DAR (Drug-to-Antibody Ratio) of about 2.04. In vitro, promiximab-DUBA exerted strong inhibitory effects on SCLC cell lines NCI-H526, NCI-H524 and NCI-H69, with IC50 values of 0.07 nmol/L, 0.18 nmol/L and 0.29 nmol/L, respectively. In vivo antitumor activity, promiximab-DUBA at the dose of 5 mg/kg and 10 mg/kg every three days with a total of three times were sufficient to induce sustained regression of NCI-H526 tumors over control treatment with promiximab. Mostly, no recurrence was observed until 65 days post treatment with promiximab-DUBA. In the NCI-H69 subcutaneous xenograft model, significant inhibition of tumor growth was also observed following administration of promiximab-DUBA at the dose of 5 mg/kg or 10 mg/kg. Moreover, body weight and histopathology of major organs (liver, spleen, heart, lung and kidney) showed no significant changes after treatment of promiximab-DUBA. In conclusion, promiximab-DUBA is highly efficacious in small cell lung cancer xenograft models, and provides a new immunotherapy approach for SCLC.

NRXN1 as a novel potential target of antibody-drug conjugates for small cell lung cancer

“…NRXN1 is expressed in a limited manner in the central nervous system (CNS) and is a favorable target, since ADCs are unable to pass through the blood-brain barrier because of their large molecular size. A CD56-mediated ADC did not induce obvious damage to the CNS in xenograft models [ 42 ]. However, given that antineuronal autoantibodies are detected in paraneoplastic neurological syndrome, possible CNS side effects should be further validated using in vivo experiments.…”

Small Cell Lung Cancer from Traditional to Innovative Therapeutics: Building a Comprehensive Network to Optimize Clinical and Translational Research

“…In a preclinical study, promiximab-duocarmycin (DUBA), a CD56 antibody conjugated to a potent DNA alkylating agent with a novel linker, showed promising results. This antibody drug conjugate (ADC) demonstrated high efficacy in SCLC xenograft models [140], suggesting that further clinical evaluation of this compound may be beneficial. Another ADC sacituzumab govitecan is comprised of a humanized mAb targeting Trop-2 (trophoblastic antigen-2), which is highly expressed in several epithelial cancers [141], fused to SN-38 (the active metabolite of irinotecan), which induces double-and single-strand DNA breaks by inhibiting topoisomerase I [142].…”

Antibody-Drug Conjugates for the Therapy of Thoracic Malignancies

“…16 The cathepsin B cleavable linker is also used in telisotuzumab vedotin and lifastuzumab vedotin which are being developed for NSCLC and promiximab-duocarmycin, which is being developed for SCLC. [17][18][19] A pH-sensitive hydrazone linker can be selectively hydrolyzed at acidic pH in lysosomes or endosomes. In sacituzumab govitecan, a pH-sensitive cleavable linker with a carbonate group attached to a tertiary carbon of the toxophore 7-ethyl-10-hydroxycamptothecin at a different position from the hydrazone linker has increased stability at physiologic pH.…”

“…36 The duocarmycin prodrug used in promiximab-duocarmycin is an alkylating agent targeting the DNA minor groove with promising preclinical anticancer activity. 19 Other classes of toxophores in preclinical testing include calicheamicin, tubulysin, a-amanitin, and doxorubicin. 31…”

“…In SCLC xenograft models, promiximab-duocarmycin has shown sufficient antitumor activity and sustained tumor regression without affecting other vital organs. 19 The anti-NaPi2b ADC, lifastuzumab vedotin, was designed to conjugate MMAE to an anti-NaPi2b antibody targeting a number of cancers including lung cancer that highly express this type II sodium-phosphate cotransporter on their cell surface. In NSCLC tumor xenograft models, this ADC has shown effective antitumor activity and satisfactory safety profile despite normal tissue expression of the targeted protein on cell surfaces.…”