ABBV-011, A Novel, Calicheamicin-Based Antibody–Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumours[
Calicheamicin-Based ADCs for Small Cell Lung Cancers
Introduction
Small cell lung cancers (SCLC) make up approximately 15% of all lung cancers. However, they are one of the most aggressive cancers with a median 5-year survival of about 7%. Typically driven by inactivating mutations in TP53 and RB1, in addition to MYC amplification, most cases of SCLC have already become metastatic by the time of diagnosis. Treatment options are limited, with platinum-based DNA damaging agents, etoposide and checkpoint inhibitors being the standard of care.
Calicheamicin, a highly toxic DNA damaging agent has been used as the payload for antibody drug conjugates (ADCs) for the treatment of haematological malignancies. The first ADC approved by the FDA was an anti-CD33 directed antibody linked to calicheamicin for the treatment of relapsed/refractory acute AML. These ADCs were linked via an acid-labile dimethylhydrazine (DMH) linker drug that had significant off-target toxicity. Calicheamicin-ADCs were evaluated in solid tumours; however, the DMG-linker resulted in toxic metabolites that limited dosing schedules and compromised any therapeutic window.
In this study by Wiedemeyer et al (Mol Cancer Ther; 21(6) June 2022) the authors described the development of a targeted ADC with an LD19.10 linker drug that does not produce the highly toxic metabolites of the DMH linker.
Main Points
- As a proof of concept, the authors conjugated LD19.10 to an anti-CD46 antibody. A panel of PDXs that expressed high levels of CD46 were used to test the ADC. PDX tumours included SCLC, TNBC, estrogen receptor–positive (ERþ) breast cancer, colorectal cancer, gastric cancer, non–small cell lung cancer (NSCLC) and pancreatic cancer.
- An 8mg/kg dose resulted in some anti-tumour activity in most of the range of patient derived (PDX) tumours. In SCLC PDX tumours, however, there was a robust reduction in tumour growth (time to progression) at the lower 2-4mg/kg dose. Using a different ADC targeting CD46 there was potent antitumour activity in all PDX tumours suggesting a specific mechanism for the LD19.10 linker in SCLC.
- To identify potential gene targets for ADC development the authors examined 66 SCLC PDXs and 188 primary SCLC samples. They used a genome wide bioinformatic screen and RNA-seq to look for membrane proteins that were co-expressed with chromogranin A (CHGA), a known marker for SCLC.
- The single pass transmembrane protein SEZ6 was identified with robust expression across a large set of SCLC PDXs and minimal expression in normal tissues. SEZ6 protein expression was confirmed in SCLC cell lines and PDXs using a validated immunohistochemistry method.
- 74 unique mouse mAbs against SEZ6 were identified from a standard hybridoma culture. 7 different epitopes were identified and their ability to kill SEZ6 overexpressing HEK293 cells was assessed using Saporin directed cytotoxicity. Antibody SC17 was chosen as the lead from a panel of humanised antibodies.
- The mature ADC, ABBV-011, was constructed using SC17 and the linker drug LD19.10. Binding affinity of the ABBV-011 was similar to SC17 alone. Cytotoxicity assays demonstrated dose-dependent killing of SEZ6 transfected HEK293 cells but not the parental cell line. Potent cytotoxicity was also detected in HEK293 cell overexpression mouse, rat and cyno SEZ6 consistent with the cross-reactivity of SC17.
- Cytotoxic activity was also confirmed in a human cell line, NCI-H69, with endogenous SEZ6 expression. No cytotoxicity was observed when NCI-H69 SEZ6 KO cells were treated with ABBV-011.
- ABBV-011 had anti-tumour activity in PDX tumours directly proportionate to the level of SEZ6 expression.
Conclusion
In Summary, current standard of care first line treatments for SCLCs include DNA damaging agents. Based on this evidence the authors suggested that calicheamicin-based ADCs could be a potential treatment option. Firstly, they identified a linker that did not produce the toxic metabolites associated with first generation calicheamicin-based ADCs. They also identified a cell-surface marker for SCLCs, SEZ6 that could be targeted by an ADC. ABBV-011 had good antitumour efficacy against SEZ6 expressing cell lines in vitro and PDX tumours in mouse models and has been put forward for evaluation in clinical trials.
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