BMS-986449 is an IKZF2 (Helios)/IKZF4 (Eos) degrader and CELMoD molecular glue. It redirects the interaction between the E3 ubiquitin ligase Cereblon and Helios/Eos in primary Treg cells, inducing their degradation, and may be utilised for anti-tumour immunotherapy.

When primary human Treg cells were co-cultured with BMS-986449 under activating conditions, transcriptional phenotype reprogramming was observed on day 8 of culture: the protein expression levels of effector molecules (such as Granzyme B) were increased, and inflammatory gene transcripts were highly expressed [1].

In tumor-bearing hCRBN-KI mice (humanized CRBN knock-in mice), daily administration of BMS-986449 as a monotherapy exhibited antitumor activity in the three tumor models (CT26, MB49, and MC38), with tumor growth inhibition (TGI) rates reaching 75%, 62%, and 42%, respectively. When BMS-986449 was used in combination with anti-PD-1 immune checkpoint blockade therapy, the therapeutic efficacy was further enhanced, and the TGI rates in the aforementioned three tumor models reached 95%, 97%, and 92%, respectively [1].
In cynomolgus monkeys, daily administration of BMS-986449 (at a dose of 0.1 mg/kg) maintained a degradation rate of Helios in circulating Treg cells at over 80% [1].