Background Lemzoparlimab (also known as TJC4) is a human anti-CD47 IgG4 antibody which blocks CD47-SIRPα interaction to enhance tumor phagocytosis. Felzartamab (also known as TJ202) is a human anti-CD38 IgG1 antibody which depletes CD38-expressing MM cells by antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Here we examined the differential gene expression in rrMM patients categorized by CD47 and CD38 expression and explored the in vitro and in vivo effects of the combination of lemzoparlimab and felzartamab in high-risk and standard-risk rrMM models.
Methods RNA-seq data from 77 bone marrow samples of recurrent MM patients in the MMRF CoMMpass study were analyzed to correlate the CD47 and CD38 expression with overall survival. Gene set enrichment analysis (GSEA) on KEGG pathways was performed for differential gene expression between CD47 high and low expressing subgroups. In vitro phagocytosis was evaluated by the treatment of lemzoparlimab and felzartamab alone or in combination using multiple high-risk and standard-risk MM cell lines with different CD38 and CD47 expression. In vivo anti-tumor activity of felzartamab and lemzoparlimab combination was evaluated in high-risk MM CDX and PDX model, respectively.
Results Higher CD47 expression was found to be correlated with worse overall survival whereas higher CD38 expression was correlated with better survival in rrMM patients who received second-line therapies. MM patients with concurrent CD47 high and CD38 low expression including those resistant to daratumumab treatment showed a significantly poorer clinical outcome as compared to other patient populations with CD47 low or CD38 high expression. CD47 expression was significantly higher in high-risk MM patients compared with that in standard risk MM patients (p<0.05 by Wilcoxon test) while CD38 expression was not different. Pathway enrichment by GSEA revealed that putative resistance mechanism against CD38-targeted therapy including tumor cell proliferation (e.g., MAPK pathway) and immune tolerance (e.g., TGF-β pathway) was up-regulated whereas antigen presentation pathway was down-regulated in CD47 high expressing MM patients, indicating the role of CD47 in CD38-targeted therapy resistance.
To further investigate the effects of dual targeting CD38 and CD47 on the killing of MM cells, we first determined the surface expression of CD47 and CD38 and molecular genetics in multiple MM cell lines which could be categorized by high-risk and standard-risk according to the mSMART3.0 guidelines. CD47 was highly expressed in high-risk MM cells as compared to standard-risk MM cells while there was no difference of CD38 expression between these two groups. Secondly, high-risk MM cells with high CD47 expression were more resistant to CD38 antibody (daratumumab or felzartamab) mediated phagocytosis as compared to standard-risk MM cells with low CD47 expression. Although the combination of felzartamab and lemzoparlimab effectively enhanced the phagocytosis across all the tested cell lines, the synergistic effect was more prominent in these daratumumab or felzartamab resistant high-risk MM cell lines with CD47 high and CD38 low expression. Third, felzartamab and lemzoparlimab combination elicited synergistic tumor regression in high-risk CDX model which was CD47 high and CD38 low while an additive anti-tumor activity was observed in another standard-risk PDX model which was CD47 and CD38 double high.
Conclusion We found high CD47 and low CD38 expression was related with poor clinical outcome in rrMM patients especially those high-risk populations. Combination of lemzoparlimab and felzartamab showed enhanced in vitro ADCP and in vivo anti-tumor efficacy in these CD47 high and CD38 low high-risk MM cells which were resistant to felzartamab or daratumumab mono-treatment. Our study provides preclinical evidence to explore the combination of lemzoparlimab and felzartamab in the treatment of high-risk MM patients.
Hayslip:I-Mab Biopharma: Current Employment, Current equity holder in publicly-traded company, Research Funding.
Asterisk with author names denotes non-ASH members.