Anti-CD20 antibodies, such as rituximab, have been a cornerstone in the treatment of non-Hodgkin’s B-cell lymphoma, offering significant therapeutic benefits to patients. However, not all patients respond favorably to rituximab; approximately 15% are refractory to the treatment, and about 25% experience a relapse within three years post-treatment.

The underlying mechanisms of resistance to rituximab are complex and multifaceted. One key factor contributing to this resistance is the inhibitory Fc receptor CD32b (FcyRIIB). This receptor is expressed on both tumor cells and immune effector cells, playing a dual role in promoting resistance. On tumor cells, CD32b mediates the internalization of rituximab, effectively removing the antibody from the cell surface and diminishing its therapeutic action. Clinically, higher levels of tumor CD32b expression have been observed to correlate inversely with patient responses to rituximab across various lymphoma subtypes, including mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).

BI-1206 is an investigational anti-CD32b IgG1 antibody designed to address this resistance mechanism. By blocking CD32b, BI-1206 prevents the internalization of rituximab, thereby enhancing its availability and prolonging its therapeutic engagement with CD20 in lymphoma cells. In non-clinical experimental models, BI-1206 has demonstrated the ability to enhance the efficacy of rituximab and overcome resistance.

The current phase I/IIa clinical trial includes R/R B-cell NHL; subtypes FL, MZL, and MCL. In this trial, safety and tolerability of both intravenous (IV) and Subcutaneous (SC) BI-1206 in combination with rituximab is evaluated. Corticosteroid pretreatment with two daily doses prior to IV administration was implemented after the first three cohorts. IV Phase 2 dose has been established and dose expansion is ongoing. SC BI-1206 dose escalation is ongoing.

In Phase IIa, BI-1206 will be evaluated in combination with rituximab and acalabrutinib, with a safety run-in followed by an expansion of up to 30 patients.

As of May 1, 2024, addition of BI-1206 to rituximab treatment shows promising efficacy in relapse or refractory follicular lymphoma, with complete response rate of 38% and overall response rate of 56%. The disease control rate of 72% was seen in 17 evaluable patients.

SC administration has been shown to improve tolerability of BI1206, and dose escalation is currently ongoing in the Phase I of this trial. In the SC arm, six patients have been treated to date with one complete response, two partial response, one stable disease out of four evaluable patients.

BI-1206 + rituximab appears to be safe and adverse drug reactions are manageable. Implementation of premedication with corticosteroids minimized risk and Treatment emergent adverse events (TEAEs) after IV administration. The most frequent related treatment-emergent adverse events after BI-1206 IV were thrombocytopenia and elevated transaminases. Thrombocytopenia ≥Grade 3 occurred in 4 out of 10 subjects without premedication, and in 6 out of 13 subjects with premedication.

All events were resolved with a median duration of 5 days. Elevated liver enzymes ≥Grade 3 occurred in 4 out of 10 subjects without premedication and 3 out of 13 subjects with premedication.

KOL insights

“The responses observed in patients are very encouraging and clearly suggest that BI-1206 may restore the response to rituximab in patients who have few treatment alternative.” – MD, United States

Conclusion 

The development of BI-1206 represents a strategic approach to improving outcomes for patients who are refractory or relapse after rituximab treatment. By targeting CD32b, BI-1206 could potentially restore or augment the anti-tumor activity of rituximab, offering a new avenue for patients who have limited options due to resistance. BI-1206 in combination with rituximab appears to be safe and adverse drug reactions are manageable. Subcutaneous administration shows great potential to mitigate TEAEs further, and to provide prolonged target engagement with increased patient convenience.

Ongoing clinical trials will further elucidate the potential of BI-1206 as a valuable addition to the therapeutic arsenal against non-Hodgkin’s B-cell lymphoma. The ROSEWOOD study (NCT03332017) found that when the anti-CD20 mAb Obinutuzumab was combined with the BTK-inhibitor zanubrutinib, the CRR in R/R FL patients increased from 19% to 39% and the ORR from 46% to 69%. Furthermore, a smaller research conducted demonstrated that acalabrutinib was well-tolerated and had encouraging response rates in FL when combined with rituximab (ASCO 2018; Abstract #7549). Owing to the promising efficacy signal of BI-1206 in combination with rituximab observed in Phase I, development will proceed into a Phase IIa setting. Given the promising results of combinatory inhibition of CD20 and BTK in R/R FL patients, addition of acalabrutinib to treatment will be explored.