Novel therapeutic agents targeting innate/inflammatory signaling for the treatment of MDS
| Therapeutic class . | Agent . | Novel features . | Patient population . | Stage of development . | Preliminary results . | NCT no. . | Ref. . |
|---|---|---|---|---|---|---|---|
| TLR signaling inh | OPN-305 | Anti-TLR2 monoclonal antibody | HMA failure lower-risk MDS | Phase 1-2 | 50% HI (6/12); 17% TI (2/12) | NCT02363491 | 53 |
| Bortezomib | TRAF6 inh via bortezomib-mediated autophagy | R/R lower and higher-risk MDS and AML; also in combination with Len, HMA, or HDACi | Phase 1-2 | 20% HI (3/15) | NCT01891968 | 55 | |
| MDSC elimination | BI 836858 | Anti-CD33 monoclonal antibody (reduce MDSCs by ADCC) | R/R lower-risk MDS (HMA naïve and HMA failure) | Phase 1-2 | N/A | NCT02240706 | 56 |
| AMV564 | CD33/CD3 BiTE | HMA failure higher-risk MDS | Phase 1 | N/A | NCT03516591 | ||
| 161533 | CD16/IL-15/CD33 TriKE | R/R higher-risk MDS, AML, or advanced SM | Phase 1-2 | N/A | NCT03214666 | ||
| NLRP3 inflammasome inhibitors | PF-06650833 | IRAK 4 inh (↓ NLRP3 transcription); synergy with BCL-2 inh | No current MDS trial | Phase 1 | N/A | NCT02996500 | |
| MCC950 | Specific NLRP3 inh (used as prototypic inh in laboratory models) | No current MDS trial | N/A | N/A | 59 | ||
| Ibrutinib | BTK inh; directly binds ASC and NLRP3; inh ASC speck formation | HMA failure higher-risk MDS; in combination with Len or AZA | Phase 1 | N/A | NCT03359460; NCT02553941 | 62 | |
| IL-1β inhibitors | Canakinumab | IL-1β neutralizing monoclonal antibody; ↓ MDSC | Planned R/R lower-risk MDS; approved for CAPS | Phase 1-2 | N/A | 75 | |
| Rilonacept | Soluble decoy receptor that binds IL-1β and IL-1α | No current MDS trial; approved for CAPS | N/A | N/A | |||
| Anakinra | Direct antagonist of the IL-1R | No current MDS trial; approved for CAPS | N/A | N/A |
| Therapeutic class . | Agent . | Novel features . | Patient population . | Stage of development . | Preliminary results . | NCT no. . | Ref. . |
|---|---|---|---|---|---|---|---|
| TLR signaling inh | OPN-305 | Anti-TLR2 monoclonal antibody | HMA failure lower-risk MDS | Phase 1-2 | 50% HI (6/12); 17% TI (2/12) | NCT02363491 | 53 |
| Bortezomib | TRAF6 inh via bortezomib-mediated autophagy | R/R lower and higher-risk MDS and AML; also in combination with Len, HMA, or HDACi | Phase 1-2 | 20% HI (3/15) | NCT01891968 | 55 | |
| MDSC elimination | BI 836858 | Anti-CD33 monoclonal antibody (reduce MDSCs by ADCC) | R/R lower-risk MDS (HMA naïve and HMA failure) | Phase 1-2 | N/A | NCT02240706 | 56 |
| AMV564 | CD33/CD3 BiTE | HMA failure higher-risk MDS | Phase 1 | N/A | NCT03516591 | ||
| 161533 | CD16/IL-15/CD33 TriKE | R/R higher-risk MDS, AML, or advanced SM | Phase 1-2 | N/A | NCT03214666 | ||
| NLRP3 inflammasome inhibitors | PF-06650833 | IRAK 4 inh (↓ NLRP3 transcription); synergy with BCL-2 inh | No current MDS trial | Phase 1 | N/A | NCT02996500 | |
| MCC950 | Specific NLRP3 inh (used as prototypic inh in laboratory models) | No current MDS trial | N/A | N/A | 59 | ||
| Ibrutinib | BTK inh; directly binds ASC and NLRP3; inh ASC speck formation | HMA failure higher-risk MDS; in combination with Len or AZA | Phase 1 | N/A | NCT03359460; NCT02553941 | 62 | |
| IL-1β inhibitors | Canakinumab | IL-1β neutralizing monoclonal antibody; ↓ MDSC | Planned R/R lower-risk MDS; approved for CAPS | Phase 1-2 | N/A | 75 | |
| Rilonacept | Soluble decoy receptor that binds IL-1β and IL-1α | No current MDS trial; approved for CAPS | N/A | N/A | |||
| Anakinra | Direct antagonist of the IL-1R | No current MDS trial; approved for CAPS | N/A | N/A |
ADCC, antibody-dependent cellular cytotoxicity; AML, acute myeloid leukemia; ASC, apoptosis-associated speck-like protein containing a caspase-recruitment domain; AZA, azacitidine; BiTE, bispecific T-cell engager; BTK, Bruton tyrosine kinase; CAPS, cryopyrin-associated periodic syndrome; HDACi, histone deacetylase inhibitor; HI, hematologic improvement; HMA, hypomethylating agent; inh, inhibitor; Len, lenalidomide; NCT, National Clinical Trial; R/R, relapse/refractory; SM, systemic mastocytosis; TI, transfusion independent; TriKE, trispecific killer cell engager. Other abbreviations are explained in Table 1.