Unlocking the Potential of ABBV-101: A Breakthrough BTK Degrader for Advanced B-Cell Malignancies

A novel BTK degrader, ABBV-101, has been introduced as a potential solution for B-cell malignancies, where current BTK inhibitors have limitations. Unlike traditional inhibitors that target the catalytic domain of BTK, ABBV-101 is designed to selectively degrade the BTK protein, affecting both its catalytic and scaffolding functions. This approach could lead to more profound and lasting effects in patients with B-cell malignancies.

Preclinical studies have demonstrated ABBV-101's effectiveness against BCR pathway-dependent models of leukemia and lymphoma, including those resistant to existing BTK inhibitors due to the BTK-C481S mutation. The compound has shown similar potency against both the wild-type BTK and the BTK-C481S mutation in human DLBCL cell lines, leading to significant inhibition of cellular growth. It has also exhibited strong activity against new BTK mutations that confer resistance to reversible inhibitors, a growing concern in clinical settings.

In vivo testing has been promising, with ABBV-101 inducing complete tumor regression in a BTK-C481S DLBCL xenograft model and significantly reducing CLL burden in a mouse model with the BTK-C481S mutation. The compound has also shown the ability to induce complete tumor regressions in several non-GCB DLBCL patient-derived xenograft models, outperforming both covalent and reversible inhibitors in terms of response depth and durability.

The combination of ABBV-101 with a BCL-2 inhibitor has been found to enhance its efficacy in CLL and DLBCL models. Furthermore, kinome and proteomics profiling indicate that ABBV-101 is highly selective, a characteristic that could contribute to better tolerability in patients.

Currently, ABBV-101 is in the first phase of clinical trials for a range of B-cell malignancies. The results from preclinical studies are encouraging, suggesting that ABBV-101 could offer a new therapeutic option for patients with B-cell malignancies, particularly those resistant to current treatments.