Pf558 the Anti-Bcma Antibody-Drug Conjugate Gsk2857916 Drives Immunogenic Cell Death and Immune-Mediated Anti-Tumor Responses, and in Combination With an Ox40 Agonist Potentiates in Vivo Activity

Abstract

survival (OS) and progression free survival (PFS) in MM patients. Furthermore, the preclinical activity of a new GPRC5DxCD3 bispecific antibody (JNJ-7564) in development for the treatment of MM was evaluated, as well as biomarkers for in vitro JNJ-7564 response. Methods: GPRC5D protein expression was assessed by flow cytometry on BM MNCs derived from healthy donors (HD) and MM patients. GPRC5D gene expression levels were analyzed in purified CD138 + MM cells derived from patients who participated in 5 large randomized clinical trials (HOVON65, MRC-IX, TT2, TT3 and APEX). MM cell lysis by JNJ-7564 (0.00064-4 µg/ml; 48 hour-incubation) was evaluated in MM cell lines and whole BM samples from newly diagnosed (ND) and relapsed/refractory (RR) MM patients. At baseline, the MNCs were characterized for the composition of T-cell subsets. T-cell activation and degranulation were measured by flow cytometry based on expression of CD25 and CD107a, respectively. Results: GPRC5D protein expression was significantly higher on MM cells compared to other BM cells, including HD plasma cells (fig 1A). GPRC5D protein expression was positively correlated with BCMA expression (r = 0.44; P = 0.02), but was independent of tumor load, and CD38 or PD-L1 expression on MM cells. Gene expression levels of GPRC5D were highly variable in MM, and independent of age and ISS stage, but were significantly higher in patients with t(4;14) or gain 1q. There was no association with OS or PFS in the 5 clinical trials (n = 1421). JNJ-7564 effectively killed GPRC5D + MM cell lines (MM1.S, UM9 (fig 1B) and RPMI8226) in a dose-dependent manner using HD peripheral blood MNCs as effector cells. Co-incubation with patient-derived BM stromal cells resulted in a modest impairment of killing capacity in MM1.S and RPMI8226 cells. In MM patient samples (n = 20), the mean lysis of MM cells with 4.0 µg/mL JNJ-7564 was 62% (range: −8-97%; fig 1C), while NK-cell and T-cell frequencies were not affected. JNJ-7564 was also effective in samples from extensively pretreated daratumumab (DARA)-refractory patients (DRMM; n = 6; median of 6 prior lines; mean lysis with 4.0 µg/mL: 70%; range: 44-97%). Maximal lysis of primary MM cells was not associated with the level of GPRC5D expression on MM cells, effector:target ratio, or frequency of regulatory T-cells. JNJ-7564-mediated MM cell lysis was associated with activation and degranulation of CD4+ and CD8+ T-cells (fig 1D).

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

“…In preclinical in vitro and in vivo models, belamaf showed anti-MM activity without affecting BCMA-negative cells and the MMAF arrested the cell cycle of malignant plasma cells at the G2/M phase, eventually leading to cell death [88]. Its afucosylated Fc fraction promotes Fc-dependent immune effector functions, mainly ADCP and ADCC [89].…”

The role of belantamab mafodotin for patients with relapsed and/or refractory multiple myeloma

“…6,8,[10][11][12][13][14][15] Preclinical studies demonstrated encouraging anti-MM activity of belamaf through several mechanisms of action including direct apoptosis through the ADC mechanism, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and immunogenic cell death. 10,11,[14][15][16] Importantly, belamaf also demonstrated the ability to rapidly eliminate MM cells while sparing normal bone marrow stromal cells and immune effector cells when treated in co-culture. 10,11 Clinical data…”

Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression

“…Belantamab mafodotin (GSK2857916) is an afucosylated, humanized IgG1 anti-B-cell maturation antigen (BCMA) mAb conjugated with monomethyl auristatin F (MMAF), which is a tubulin polymerization inhibitor [ 147 ]. Both parts (anti-BCMA antibody and MMAF toxin) are linked through a non-cleavable maleimidocaproyl linker, which provides better plasma stability of the compound without losing any property and without any nonspecific toxicity [ 148 ]. Belantamab mafodotin is the first anti-BCMA ADC approved by the FDA as a single agent for relapsed/refractory multiple myeloma (RRMM) patients who have received at least four prior therapies [ 149 ].…”

“…Belantamab mafodotin exerts its antimyeloma effect through four known mechanisms: (i) ADCC mediated by NK cells; (ii) recruitment of macrophages to promote ADCP; (iii) disruption of microtubules and subsequent G 2 /M cell-cycle arrest followed by apoptosis after the release of the MMAF toxin in the cytoplasm of myeloma cells [ 147 ] and (iv) induction of immunogenic cell death (ICD) [ 148 ], which is a mechanism characterized by the ability of dying cells to elicit robust adaptive immune responses against altered self-antigens or cancer-derived neo-epitopes [ 154 ]. In relation to the latter mechanism, preliminary data indicates that treatment of myeloma cells with belantamab mafodotin promotes the exposure of calreticulin (CALR) on their surface and the release of HMGB1, which subsequently induce the maturation and activation of DCs and eventually the activation of T cells [ 148 ].…”