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Table 4 Current status of therapeutic agents targeting ligands activating checkpoint receptors

From: Reactivation of dormant anti-tumor immunity – a clinical perspective of therapeutic immune checkpoint modulation

Drug Target

(Synonym)

Effect on T-cells and immune system

Compound

(Synonym)

Compound

(Trade name)

Drug type

(application)

Status

Indication

CD80 (B7-1)

CD86 (B7-2)

T-cell costimulation blocker, inhibits T-cell proliferation and production of cytokines

Belatacept

(LEA29Y)

BMS

(Nulojix)

CTLA4 fusion-Ig, costimulation blocker

FDA approval 15.11.2011

EMA approval 07.07.2011

Prophylaxis of renal graft rejection

Prophylaxis of renal graft rejection

Abatacept

BMS

(Orencia)

CTLA4 fusion-Ig,

costimulation blocker

FDA approval 31.07.2011

EMA approval 25.01.2010

Rhematoid arthritis; Polyarticular juvenile idiopathic arthritis

CD80

Activates ADCC on B-NHL cells with upregulated CD80

Galiximab

(IDEC-114)

Biogen

Humanized MAb IgG1, (i.v.)

Phase I/II

Phase II

Untreated follicular lymphoma

Relapsed/refractory M. Hodgkin

CD80

DNMT1

Upregulation of CD80 on cancer cells - > costimulatory activation of T-cells

Decitabine

Janssen-Cilag (Dacogen)

Deoxycytidine analogue, i.v. (D1-5, Q6W)

FDA approval 02.05.2006

EMA approval 28.09.2012

Myelodysplastic syndromes

Acute myeloid leukemia

CD86

HDAC

Upregulation of CD86 on cancer cells, HDAC-I - > costimulatory activation of T-cells

Romidepsin

(FR901228)

Gloucester Pharmaceuticals, Celgene (Istodax)

Depsipeptide, (i.v. Q1W)

FDA approval 05.11.2009

EMA refused approval 09.07.2012

Cutaneous T-NHL, PTCL

CD137-L

Induction of differentiation of AML cell samples in vitro

-

-

Recombinant CD137-L protein

Preclinical

In vitro

CD252 (OX40-L)

Binds and activates Ox40 by mimicking Ox40-L - > proliferation of TAA specific T-effector cells - > activation of anti-tumor immune response

MEDI-6383

MedImmune

Fusion protein

Phase I

Advanced solid tumors

CD252 (OX40-L)

Binds and inhibits Ox40L and the interaction with Ox40 - > inhibition of allergen induced immune response

Oxelumab (huMAb OX40L)

(R4930)

Genentech

Human MAb IgG1, (i.v.)

Phase II

Mild allergic asthma

CD276 (B7-H3)

Inhibits CD276

Enoblituzumab

(MGA-271)

MacroGenics

Humanized MAb IgG1ĸ, (i.v.)

Phase I

B7-H3 expressing refractory solid tumors

CD276 (B7-H3)

CD3

Redirection of T-cells to kill B7-H3 overexpressing tumor cells

MGD-009

MacroGenics

Dual affinity retargeting protein

Phase I

B7-H3 expressing unresectable or metastatic solid tumors

  1. MAb indicates monoclonal antibody, i.v. intravenous, FDA Agency for Food and Drug Administraton, EMA European Medicines Agency, ADCC antibody dependent cellular cytotoxicity, NHL non-Hodgkin lymphoma, PTCL peripheral T-cell lymphoma, TAA tumor associated antigen