Table 9.
Future mAb targets for myeloid neoplasms.
| Target | mAb | Mechanism/function | Preclinical results | Clinical trials | Reference |
|---|---|---|---|---|---|
| CD26 (dipeptidyl peptidase IV) | – | Expression on CML LSCs | CD26+ stem cells reconstitute BCR-ABL1+ leukemia, whereas CD26− stem cells reconstitute normal hematopoiesis; targeting of CD26 by gliptins suppresses expansion of CML cells and improves engraftment of normal HSCs during aHSCT | Sitagliptin in aHSCT for AML: NCT00862719 NCT01720264 |
(313, 314) |
| CD37 | AGS67E (anti-CD37 auristatin E ADC) BI 836826 TRU-016 |
Expression on AML blasts and CD34+CD38− LSCs | AGS67E induces cytotoxicity in AML cell lines and shows antitumor effects in AML xenografts | – CLL/NHL: NCT02538614 NCT00614042 |
(315) |
| CD43 | AT1413 | Expression on AML blasts and MDS cells | AT1413, a donor-derived antibody, was discovered in a patient with long-lasting GvL after aHSCT for AML. Induction of ADCC and CDC in vitro and in xenografts | – | (316) |
| CD52 | Alemtuzumab | Highly expressed on blasts in subset of AML patients with high EVI1 expression and in MDS with isolated del(5q) | CDC and ADCC in vitro, suppression of growth and increased survival in xenografts | Numerous clinical trials in the setting of aHSCT for AML and MDS | (317, 318) |
| CD82 | Anti-CD82 | Promotes adhesion of CD34+CD38− AML LSCs to BM microenvironment | Mobilization of CD34+ cells and chemosensitization to cytarabine | – | (319) |
| CD93 | Anti-CD93 | Expression on CD34+CD38− LSCs in subset of AML patients with MLL rearrangement | CD93+ AML LSCs are cycling and CD93 is required for engraftment in xenografts | – | (320) |
| CD96 (TACTILE) | Mini-Ab (scFv-IgG1 Fc) | Expression on AML blasts | CD96 expression associated with poor prognosis; NK cell-mediated ADCC in vitro | – | (296, 297) |
| CD105 (endoglin) | TRC105 | Expression on AML blasts | Blocks engraftment in xenografts | – | (299) |
| CD133 | AC133 W6B3 293C3 |
Expression on a wide variety of tumors including AML | NK cell-mediated ADCC in vitro and in vivo in xenografts with matched NK cell donors | – | (321, 322) |
| CD134 (OX-40) | PF-04518600 | T cell costimulatory molecule CD134 ligand expressed on NK cells |
CD134 signaling on AML blasts promotes proliferation and cytokine secretion | NCT03390296 | (323) |
| CD135 (FLT3) | FLT3 × CD3 BiTE | Receptor tyrosine kinase expressed on myeloid cells and progenitors | T cell-mediated killing of malignant blasts in PBMC cultures from AML patients | – | (324) |
| CD137 (4-1BB) | Utomilumab | Expressed on AML blasts (both CD137 and CD137 ligand) CD137 ligand reverse signaling induces differentiation in AML blasts |
CD137 expression correlates with favorable outcome in AML Blocking CD137 restores NK cell function in AML |
NCT03390296 | (325–327) |
| CD157 | MEN1112 | Expression on AML blasts and hematopoietic cells | NK cell-mediated ADCC against AML blasts in vitro | NCT02353143 | (306, 307) |
| CD200 | Samalizumab | Inhibitory ligand for CD200R expressed on memory T cells | Overexpressed in AML, correlates with high Treg cell frequency | NCT03013998 | (309–312) |
| CD223 (LAG-3) | IMP321 (soluble CD223) | Co-inhibitory molecule expressed on T cells and NK cells | – Several clinical trials in viral infections and solid tumors |
(328) | |
| CD276 (B7-H3) | Enoblituzumab MGD009 (B7-H3 × CD3 DART) |
Overexpression on tumor cells and vasculature | Direct tumor cell killing and destruction of tumor-associated vasculature by anti-B7-H3 ADCs | – Several clinical trials in solid tumors |
(329) |
| CD278 (ICOS) | – | T cell costimulatory molecule | Continuous co-stimulation by ICOS ligand (B7-H2) expressed on subset of AML cells leads to functional exhaustion of CD4+ T cells | – | (189, 330) |
| CD300f (IREM-1) | Anti-CD300f | ITIM-containing molecule with high expression on myeloid cells and AML blasts | ADCC and CDC in vitro; tumor growth delay and inhibition of engraftment in AML xenografts | – | (331) |
| F1F0-ATPase β | McAb7E10 | Ectopic expression on AML cell lines | Inhibition of ATP synthesis resulting in reduced proliferation in vitro | – | (332) |
| FcγR | Anti-CD32 Anti-CD64 Pseudomonas exotoxin ADC |
Expression on CD34+CD38− LSCs (CD32) CD64 expressed on U937 AML cell line |
Not expressed on healthy HSCs, engraftment not affected Elimination of U937 cells in xenografts |
– – |
(34) (282) |
| IL1RAP (IL1R3) | Anti-IL1RAP | Expression on AML and CML LSCs | Blocks IL-1-mediated proliferation, induces ADCC | NCT02842320 | (285–289) |
| GITR (TNFRSF18) | GITR-Ig fusion protein | T cell costimulatory molecule Inhibitory receptor in human NK cells |
GITR ligand expressed on AML blasts and soluble GITR ligand in serum impair NK cell function in AML GITR-Ig fusion protein enhances NK cell-mediated ADCC against AML |
– | (333–335) |
| HMW-MAA | Anti-HMW-MAA | Expression on blasts in subset of AML patients with 11q23 aberrations | Anti-HMW-MAA mAbs enhanced the anti-proliferative effects of cytarabine; no effect on survival in xenografts | – | (336) |
| PR1 peptide on HLA-A2 WT1 peptide on HLA-A2 |
TCR-mimics: 8F4 ESKAM |
Binding to AML blasts; CDC | Effective killing of human AML blasts in xenografts | – | (278, 279) (280, 281) |
| SAIL (surface antigen in leukemia) | 7-1C 67-7A (anti-SAIL auristatin F ADCs) |
Wide expression in hematological cancers including AML | AML cell killing in vitro; inhibition of tumor growth in xenografts | – | (337) |
| TIGIT (T cell Ig and ITIM domain) | Anti-TIGIT | T cell co-inhibitory molecule | High TIGIT expression on CD8+ T cells in AML patients is a marker of exhaustion and correlates with poor outcome | – | (338) |
| U5 snRNP200 | U5 snRNP200 complex-specific antibodies | U5 snRNP200 complex is aberrantly expressed on cell surface in AML blasts | Killing of AML cells by disruption of cell membrane integrity in vitro; AML growth inhibition in xenografts | – | (339) |
| VISTA (V domain Ig suppressor of T cell activation) | Anti-VISTA | T cell co-inhibitory molecule | Expression on AML blasts in a subset of patients VISTA knockout mice are more resistant to syngeneic AML |
– | (340) (341) |
ADA, anti-drug antibodies; ADC, antibody–drug conjugate; ADCC, antibody-dependent cell-mediated cytotoxicity; aHSCT, allogeneic hematopoietic stem cell transplantation; AML, acute myeloid leukemia; BiTE, bispecific T cell engager; BM, bone marrow; CDC, complement-dependent cytotoxicity; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; DART, dual affinity retargeting; FcγR, Fc γ receptor; HMW-MAA, high molecular weight melanoma-associated antigen; ICOS, inducible T cell costimulator; Ig, immunoglobulin; IL1RAP, IL-1 receptor accessory protein; ITIM, immunoreceptor tyrosine-based inhibitory motif; LAG-3, lymphocyte activation gene-3; LSCs, leukemic stem cells; mAb, monoclonal antibody; MDS, myelodysplastic syndrome; NK, natural killer; NHL, non-Hodgkin lymphoma; PBMCs, peripheral blood mononuclear cells; TCR, T cell receptor; Treg cell, CD4+FOXP3+ regulatory T cell; GvL, graft-versus-leukemia effect.