Table 4.

Characteristics of antibodies directed to immune checkpoint receptors.

Target/expression	mAb (commercial name/originator)	IgG class	MOA	Active indications in HMs (highest phase)	References
Inhibitory receptors
Programmed death-1 (PD-1)/T-cells, NK cells, NKT cells, Treg and B-cells	Nivolumab, BMS-936558, MDX-1106 (Opdivo/Medarex; Ono Pharmaceutical)	Fh IgG4	Blocks binding of PD-1 to PD-L1 and PD-L2 thus enhancing anti-tumor immunity.	Approved (HL)	(83–88)
				III (MM/NCT02726581 aR)
				II–III (AML/NCT02275533 bR)
				II (CLL/NCT 02420912 aR)
				II (DLBCL/NCT02038933 bANR)
				II (FL/NCT02038946 bANR)
				I–II (B-NHL, T-NHL/NCT02985554 bR)
				I (CML/NCT02011945 aANR)
				I (FL/NCT03245021 aNYR)
				I (B-ALL/NCT02819804 aR)
	Pembrolizumab, MK-3475 (Keytruda/Merck & Co; The Leukemia & Lymphoma Society)	Hz IgG4	Blocks binding of PD-1 to PD-L1 and PD-L2 thus enhancing anti-tumor immunity.	III (HL/NCT02684292b R)
				II–III (MM/NCT02906332 aANR)
				II (DLBCL/NCT02362997 bR)
				II (FL/NCT02446457 aR)
				II (T-NHL, NK-L/NCT03021057 bANR)
				II (ALL/NCT02767934b R)
				II (AML/NCT02768792 bR)
				II (MF/SS/NCT02243579 bANR)
				II (CLL/NCT02332980 aR)
				I–II (MCL/NCT03153202 aR)
	Pidilizumab; CT-011, MDV9300 (CureTech)	Hz IgG4	Blocks binding of PD-1 to PD-L1 and PD-L2 thus enhancing anti-tumor immunity.	II (MM/NCT01067287 aANR)
				II (FL/NCT00904722 aC)
				II (DLBCL/NCT02530125 bANR)
				II (AML/NCT01096602 aANR)
				I–II (MM/NCT02077959 aANR)
	MEDI0680, AMP-514 (Amplimmune)	Hz IgG4	Blocks binding of PD-1 to PD-L1 and PD-L2 thus enhancing anti-tumor immunity.	I–II (B-NHL, DLBCL/NCT02271945 aC)
	REGN2810 (Regeneron Pharmaceuticals)	Fh IgG4	Blocks binding of PD-1 to PD-L1 and PD-L2 thus enhancing anti-tumor immunity.	I–II (B-NHL, HL/NCT02651662 aR)
				I–II (MM/NCT03194867 aNYR)
	PDR001 (Novartis)	Hz IgG4	Blocks binding of PD-1 to PD-L1 and PD-L2 thus enhancing anti-tumor immunity.	II (DLBCL/NCT03207867 aNYR)
				I (AML/NCT03066648 aR)
				I (MM/NCT03111992 aR)
	BGB-A317 (BeiGene)	Hz IgG4	Blocks binding of PD-1 to PD-L1 and PD-L2 thus enhancing anti-tumor immunity.	II (HL/NCT03209973 bR)
				I (B-NHL/NCT02795182 aR)
	SHR-1210 (Jiangsu Hengrui Medicine Co.)	Fh IgG4	Blocks binding of PD-1 to PD-L1 and PD-L2 thus enhancing anti-tumor immunity.	II (HL/NCT03155425 bNYR)
	Js001 (Shanghai Junshi Biosciences)	Hz mAb	Blocks binding of PD-1 to PD-L1 and PD-L2 thus enhancing anti-tumor immunity.	I (Lymphoma/NCT02836834 bR)
PD-L1 (CD274 or B7-H1)/tumor cells	Atezolizumab, MPDL-3280A, RG7446 (Tecentriq/Genentech)	Hz IgG1	Glyco-Fc	Blocks PD-L1/PD-1 interaction thus enhancing antitumor immunity.	(89–91)
				II (HL/NCT03120676 bR)
				II (CLL/NCT02846623 aR)
				I–II (DLBCL/NCT02926833 aR)
				I–II (AML/NCT02935361 aR)
				I–II (CML/NCT02935361aR)
				I (FL/NCT02220842 aR)
				I (MM/NCT02784483 bR)
	BMS-936559, MDX-1105 (Medarex)	Fh IgG4	Blocks PD-L1/PD-1 interaction thus enhancing antitumor immunity.	I (HL, NHL, CML, MM/NCT01452334 bW)
	Durvalumab, MEDI-4736 (Medimmune)	Fh IgG1	Blocks PD-L1/PD-1 interaction thus enhancing antitumor immunity.	II (AML/NCT02775903 aR)
				II (DLBCL/NCT03003520 aR)
		Glyco-Fc	ADCC
				II (MM/NCT03000452 aR)
				II (NK-T Lymphoma/NCT03054532 aNYR)
				I–II (CLL/NCT02733042 aR)
				I–II (NK-T Lymphoma/NCT02556463 aR)
				I–II (FL/NCT02401048 aANR)
	Avelumab, MSB0010718C (Bavencio/EMD Serono; Merck KGaA)	Fh IgG1	Blocks PD-L1/PD-1 interaction thus enhancing antitumor immunity.	III (DLBCL/NCT02951156 a R)
				II (T-NHL/NCT03046953 b NYR)
				I–II (AML/NCT02953561 a R)
				I–II (B-NHL/NCT03169790 a NYR)
				I (HL/NCT02603419 bR)
CTLA-4 (Cytotoxic T lymphocyte-associated antigen 4, CD152)/T-cells, Treg, NK cells	Ipilimumab (Yervoy/Medarex)|	Fh IgG1	Blocks the interaction of CTLA-4 with CD80/CD86 thus enhancing antitumor immunity.	II (AML/NCT02397720 aR)	(83, 92, 93)
				I–II (HL/NCT01896999 aR)
				I–II (MM/NCT02681302 aR)
				I (CML/NCT00732186 aW)
				I (B-NHL/NCT01729806 aANR)
				I (B-ALL/NCT02879695 bR)
	Tremelimumab, CP-675,206 (Pfizer)	Fh IgG2	Blocks the interaction of CTLA-4 with CD80/CD86 thus enhancing antitumor immunity.	I–II (B-NHL/NCT02205333 aT)
				I (DLBCL/NCT02549651 aR)
				I (MM/NCT02716805 aR)
KIR2D (killer inhibitory receptor 2D)/NK cells	Lirilumab, IPH2102 (Innate Pharma, Novo Nordisk)	Fh IgG4	Blocks the interacion of HLAC with KIR2D thus augmenting NK-cell activity.	II (AML/NCT01687387 bC) disc.	(94, 95)
				II (CLL/NCT02481297 aANR)
				I (MM/NCT02252263 aANR)
NKG2A (CD94)/NK cells, CTLs	Monalizumab, IPH2201 (Innate Pharma; Novo Nordisk)	Hz IgG4	Blocks the interaction of HLA-E with NKG2A thus augmenting NK cells and CTLs reactivity.	I–II (CLL/NCT02557516 aR)	(96, 97)
				I (HMs/NCT02921685 aR)
KIR3DL2 (killer inhibitory receptor 3DL2; CD158k)/Tumor cells	IPH4102 (University of Genoa/Innate Pharma)	Hz IgG1	ADCC	I (CTCL/NCT02593045 bR)	(98)
			ADCP
			Blocks KIR3DL2.
LAG3 (lymphocyte-activated gene-3, CD223)/Th cells, Treg	BMS-986016 (Bristol-Myers Squibb)	Fh IgG4	Blocks the binding of LAG3 to MHC-II thus decreasing tumor suppressive activity.	I/II (HL/NCT02061761 aR)	(99)
				I/II (DLBCL/NCT02061761 aR)
				I (CLL, MM/NCT02061761 bR)
TIM-3 (T-cell immunoglobulin- and mucin-domain-containing molecule 3)/T-cells, NK cells, monocytes	MBG453 (Novartis Pharmaceuticals)	Hz IgG4	Blocks TIM-3/Galectin-9 interaction thus enhancing Th1 responses and abrogating Treg suppressive functions.	I (AML/NCT03066648 aR)	(100)
CD200 (OX-2)/Tumor cells	Samalizumab, ALXN6000 (Alexion Pharmaceuticals)	Hz IgG2/4	Blocks CD200/CD200R interactions, restoring CTLs functions and antitumor immunity.	I–II (AML/NCT03013998 aR)	(101)
				I–II (CLL and MM/NCT00648739 aC) disc.
Costimulatory receptors
CD137 (4-1BB)/T-cells, Treg, DCs, NK cells, NKT cells	Urelumab, BMS-663513 (Medarex)	Fh IgG4	Mimicks activation of CD137 mediated by CD137L (4-1BBL) inducing CTLs and NK cells activation.	II (CLL/NCT02420938 aW)	(102–104)
				I–II (B-NHL/NCT02253992 aR)
				I (B-NHL/NCT01471210 bC)
				I (MM/NCT02252263 aANR)
	Utomilumab, PF-05082566 (Pfizer)	Fh IgG2	Mimicks activation of CD137 mediated by CD137L (4-1BBL) inducing CTLs and NK cells activation.	III (DLBCL/NCT02951156 aR)
				I (FL/NCT01307267 aR)
OX40 (CD134)/T-cells, Treg	MEDI6469 (AgonOx; Providence Cancer Center)	m IgG1	OX40 triggering stimulates T-cells and blocks/depletes Treg	I–II (B-cell lymphomas/NCT02205333 aT)	(105)
				Replaced by Tavolixizumab (MEDI0562)
CD27/T-cells, B-cells, NKs	Varlilumab, CDX-1127 (Celldex Therapeutics Inc.)	Fh IgG1	Mimicks CD27-CD70 interactions which accelerate NK-mediated tumor clearance while generating an adaptive immune response	II (DLBCL/NCT03038672 aNYR)	(106)
				I (B-NHL/T-NHL/NCT01460134 bANR)
CD70/T-cells, B-cells, mDC, tumor cells	ARGX-110 (arGEN-X)	Hz IgG1	ADCC	I–II (AML/MDS/NCT03030612 aR)	(107, 108)
		Glyco-Fc	ADCP
			CDC
			Blocks proliferation/survival of malignant cells.
			Innhibits activation/proliferation of CD27-positive T-reg.
CD80 (B7-1)/APCs, tumor cells	Galiximab, IDEC-114 (Biogen Idec)	Pz IgG1	ADCC	III (FL/NCT00363636 aT, NCT00384150 aT) disc.	(109, 110)
			PCD	II (B-NHL/NCT00516217 bC) disc.
			Inhibition of CD80 signaling
CD40/APCs tumor cells	Lucatumumab, CHIR-12.12, HCD-122 (Novartis; XOMA)	Fh IgG1	ADCC	II (MM/NCT00231166 bC) disc.	(111–115)
				I–II (NCT00670592 aC) disc.
			Antagonizes CD40L-mediated proliferation and survival
				I (CLL/NCT00108108 aT) disc.
				I (FL/NCT01275209 aC) disc.
	Dacetuzumab, SGN-40 (Seattle Genetics)	Hz IgG1	ADCC, ADCP	II (DLBCL/NCT00435916 bC, NCT00529503aC)
			Partial agonist that triggers both cellular proliferation and activation in APCs which subsequently activate B-cells and T-cells
				I–II (CLL/NCT00283101 bC)
				I (MM/NCT00079716 b C, NCT00664898aC)
	SEA-CD40, SEA-1C10 (Seattle Genetics)	Hz IgG1	ADCC	I (B-NHLs, HL/NCT02376699 a R)
	Derived from dacetuzumab	Glyco-Fc	Agonist that triggers both cellular proliferation and activation in APCs which subsequently activate B-cells and T-cells
	ChiLob 7/4 (University of Southampton)	Ch IgG1	CDC, ADCC	I (DLBCL/NCT01561911 bC)
			Agonist that triggers both cellular proliferation and activation in APCs which subsequently activate B-cells and T-cells
GITR (glucocorticoid-induced tumor necrosis factor receptor family-related gene)/NK cells, Th cells, CTLs, B-cells, APCs, Treg	GWN323 (Novartis)	Fh IgG1	Agonist that induces signaling through GITR abrogating Treg mediated suppression and enhancing Th, CTLs and NK cells proliferation and activation	I (B-cell lymphomas/NCT02740270 a R)	(116, 117)
		ADCC
CD47/phagocytes and DCs	Hu5F9-G4 (Stanford University)	Hz IgG4	Blocks CD47	I–II (B-NHL/NCT02953509 aR)	(118, 119)
				I (AML,MDS/NCT02678338 bR, NCT03248479 bNYR)
	CC-90002, INBRX-103 (Inhibrx)	Hz IgG	Blocks CD47	I (AML/MDS/NCT02641002 bR)
			ADCP?
				I (B-NHL/NCT02367196 aR)

Antibodies that reached clinical studies.

^aCombined therapy.

^bMonotherapy.

mAb, monoclonal antibody; MOA, mechanisms of action; HMs, hematological malignancies; Ch, human–mouse chimeric; Fh, fully human; Hz, humanized; Pz, Human-primate chimeric; m, mouse; Glyco-Fc, glycoengineered Fc fragment; CDC, complement-dependent cytotoxicity; ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cell-mediated phagoytosis; PCD, programmed cell death; HL, Hodgkin’s lymphoma MM, multiple myeloma; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; B-NHL, B-cell non-Hodgkin’s lymphoma; T-NHL, T-cell non-Hodgkin’s lymphoma; CML, chronic myeloid leukemia; B-ALL, B-cell acute lymphoblastic leukemia; NK-L, NK-cells lymphoma; MF, mycosis fungoides; SS, Sézary syndrome; MCL, mantle cell lymphoma; CTCL, cutaneous T-cell lymphoma; MDS, myelodysplastic syndrome; Treg, regulatory T-cells; Th, T helper cells; CTLs, cytotoxic T-cell lymphocytes; APCs, antigen presenting cells; DC, dendritic cells; disc., discontinued in hematological malignancies; NCT, number of clinical trial (clinicaltrials.gov); C, completed; R, recruiting; T, terminated; ANR, active non-recruiting; NYR, not yet recruiting; T, terminated; S, suspended; W, withdrawn.