serclutamab talirine (ABBV-321)

Serclutamab talirine (Ser-T, formerly ABBV-321) is an antibody-drug conjugate consisting of an antibody (AM-1-ABT-806) directed against activated epidermal growth factor receptor (EGFR) and a pyrrolobenzodiazepine dimer. Ser-T monotherapy at doses up to 50 μg/kg initial dose, followed by 25 μg/kg Q4W demonstrated a tolerable safety profile with minimal antitumor activity observed in patients with glioblastoma. The glioblastoma dose-expansion cohort was closed due to a lack of efficacy (NCT03234712).

CED of Depatux-M is well tolerated and results in extended survival in orthotopic GBM PDXs. In contrast, CED of Ser-T was associated with a much narrower therapeutic window.

P1, N=62, Completed, AbbVie | Active, not recruiting --> Completed

P1, N=62, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting | N=120 --> 62

The dramatic tumor regressions achieved using combined agents in pre-clinical TNBC models underscore the abilities of BCL-2/X antagonists to enhance the effectiveness of EGFR-targeted ADCs and highlight the clinical potential for usage of such targeted ADCs to alleviate toxicities associated with combinations of BCL-2/X inhibitors and systemic chemotherapies.

ABBV-321 follows the development of related EGFR targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). Collectively, these data suggest that ABBV-321 may offer an extended breadth of efficacy relative to other EGFR ADCs while extending utility to multiple EGFR-expressing tumor indications. Despite its highly potent PBD dimer payload, the tumor selectivity of ABBV-321 - coupled with its pharmacology, toxicology and pharmacokinetic profiles - support continuation of ongoing Phase 1 clinical trials in patients with advanced EGFR-expressing malignancies.

P1, N=120, Recruiting, AbbVie | Trial completion date: Jan 2023 --> May 2021 | Trial primary completion date: Jan 2023 --> May 2021

P1, N=120, Recruiting, AbbVie | Trial completion date: Sep 2025 --> Jan 2023 | Trial primary completion date: Mar 2024 --> Jan 2023

The dose-escalation phase has been completed; screening and enrollment for the expansion phase of the study in NSCLC and HNSCC is underway. Research Funding: AbbVie, Inc.

Tumor specific EGFR-targeted antibodies (ABT-806) and their antibody-drug conjugates (ADC:414;321), which eliminate side effects associated with systemic anti-EGFR treatments, represent promising alternative therapeutic approaches. Notably, this strategy avoids the toxicities associated with systemic chemotherapy and BCL-2/XL -inhibitors. These results also highlight the translational relevance of 321+263, within the context of EGFR-expressing TNBC.