BHV-1100, a bispecific antibody recruiting molecule

Within the field of targeted immunotherapies, novel strategies to direct immune effectors against multiple myeloma (MM) cells continue to be explored. Current challenges include identifying new targets, simplifying and improving manufacturing processes and access, and facilitating the administration of immunotherapeutic agents without compromising their efficacy and while prioritizing a safe profile.¹

BHV-1100 (previously known as KP1237) is an antibody-recruiting molecule (ARM).^2,3 ARMs bind to endogenous antibodies and direct them toward cancerous cells.² Fully synthetic ARMs offer advantages over traditional biologics, such as monoclonal antibodies, including the potential for oral administration.² In the case of BHV-1100, the ARM platform provides a bispecific antigen-targeting to endogenous antibodies and MM cells.²

Mechanism of action

As part of the innate immune system, natural killer (NK) cells target and show a strong cytolytic function against physiologically stressed cells, such as cancer cells; however, tumor cells can evade detection.² BHV-1100 targets the MM cell-surface protein CD38 and recruits NK cells to destroy the tumor.² As a bispecific molecule, BHV-1100 binds to both CD38 and human immunoglobulin (Ig), as shown in Figure 1.² When close, NK cells bind to the Fc portion of Ig and activate the antibody-dependent tumor lysis.² To enhance this effect, BHV-1100 can be combined with primed autologous cytokine-induced memory-like (CIML) NK cells. Rastelli et al. have shown a statistically significant increase in specific killing when BHV-1100 and CIML NK are combined ex vivo, without the necessity for genetic engineering.³

Figure 1. The mechanism of action of BHV-1100*

A The structure of BHV-1100. B BHV-1100 binds to Ig and CD38 receptors on MM cells, recruiting NK cells and activating antibody-dependent tumor lysis.
Ig, immunoglobulin; MM, multiple myeloma; NK, natural killer.
*Adapted from Biohavenpharma.com.²

Regulatory status

An ongoing phase Ia/Ib clinical trial (NCT04634435) is assessing potential adverse events associated with BHV-1100 and its initial efficacy in newly diagnosed patients with MM eligible for autologous hematopoietic stem cell transplant (auto-HSCT).⁴ The trial is enrolling patients in first remission before auto-SCT who have minimal residual disease; patients receive BHV-1100 in combination with CIML NK cells and low-dose interleukin-2 (IL-2).⁴ The estimated primary completion date is June 30, 2023.⁴ The U.S. Food and Drug Administration (FDA) has previously provided orphan drug designation for BHV-1100 in MM.⁵