Potent Effects of Lenalidomide-Conjugated Anti-CD38 Antibody-Drug Conjugate (TE-1146) on Multiple Myeloma Cells Isolated from Patients

Background: Despite available therapies such as proteasome inhibitors, antibodies, and immunomodulators, multiple myeloma (MM) remains incurable, with patients often experiencing relapses and severe side effects. To address this issue, we employed a proprietary HighDAR platform and developed TE-1146, which is a site-specific lenalidomide (Len)-conjugated antibody-drug conjugate (ADC) targeting CD38 on MM cells. TE-1146 utilizes cleavable linkers recognized by lysosomal cathepsin B and carries six Len molecules. Studies have shown that TE-1146 has stronger direct cytotoxicity than the combination of daratumumab (Dara) and Len, while maintaining similar Fc-mediated effects such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP). Additionally, TE-1146 has a long half-life (t_1/2: 11.1 days) in healthy mice and demonstrates superior anti-tumor efficacy in human MM cell line-derived xenograft mouse models compared to the Dara and Len combination.

Methods: This study evaluates the efficacy of TE-1146 using human MM cells isolated from bone marrow samples obtained from patients between July 2023 and May 2024. Fifteen samples were categorized into three subgroups (5 samples each): (1) from treatment-naïve patients, (2) from relapsed patients without prior Dara/Len treatments, and (3) from relapsed patients with prior Dara/Len treatments. Isolated MM cells were treated with TE-1146 or Dara/Len combination, and cytotoxicity was assessed.

Results: Of the 15 screened samples, 14 were eligible for the study, all expressing both CD138 and CD38. In subgroup 1 (treatment-naïve patients), among 5 eligible samples, TE-1146 achieved a 100% cytotoxic response with a mean IC₅₀ value of 0.05 nM. In subgroup 2 (patients who relapsed after bortezomib, thalidomide, and dexamethasone [VTD] regimens, without prior Dara/Len treatment), all 4 eligible samples exhibited a 100% cytotoxic response with a mean IC₅₀ value of 0.02 nM. In subgroup 3 (relapsed, with prior Dara/Len treatment, 5 eligible samples), one sample responded to TE-1146 treatment with an IC₅₀ value of 1.96 nM. In subgroups 1 and 2, TE-1146 exhibited at least 100-fold greater MM cell lysis compared to Dara, Len, or their combination, based on IC₅₀ values. Nevertheless, in subgroup 3, TE-1146 showed limited efficacy, likely due to developed resistance to Dara or Len.

Conclusion: This study demonstrates that TE-1146 enhanced direct cytotoxicity, significantly improving efficacy over the Dara/Len combination while potentially reducing the required dosage and associated side effects of Len. These results support further development and clinical evaluation of TE-1146 ADC as a promising treatment for MM.

Jiang:Far Eastern Memorial Hospital: Current Employment. Lin:Far Eastern Memorial Hospital: Current Employment. Cheng:T-E Meds, Inc.,: Current Employment. Yu:T-E Meds, Inc.,: Current Employment. Chang:T-E Meds, Inc.,: Current Employment. Chu:T-E Meds, Inc.,: Current Employment. Yu:Far Eastern Memorial Hospital,: Current Employment.