Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies

Abstract

Key Points• Blockade of inhibitory KIRs with MHC class I antigens on lymphoma cells by anti-KIR antibodies augments NK-cell spontaneous cytotoxicity.• In combination with anti-CD20 mAbs, anti-KIR induces enhanced NK cell-mediated, rituximab-dependent cytotoxicity against lymphoma.

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…Immune‐modulation therapies that alter NK and T‐cell function are already in development. For example Lirilumab, the monoclonal antibody that binds KIR, is currently in a phase II clinical trial for lymphoma 237. By blocking the interaction of inhibitory KIR with their HLA class I ligands this antibody facilitates activation of NK cells by impeding inhibitory signalling, potentially promoting destruction of tumour cells.…”

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response

“…First, in vivo blockade of NK cell inhibitory receptors has been attempted in mice using F(ab 0 ) 2 fragments. This approach, analogous to checkpoint blockade in T cells (6), resulted in increased rejection of MHC class I-expressing malignant cells caused by a liberated NK cell response to leukemia cells (7)(8)(9). This strategy has now been tested as anti-KIR therapy in clinical trials: a phase I trial for acute myeloid leukemia (AML) and a phase II trial for myeloma (10)(11)(12).…”

Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell–dependent cytotoxicity

“…The fulllength protein sequence of the fusokine was further confirmed by mass spectrometry analysis (data not shown). For large-scale fusokine production, proteins secreted from stably transfected 293T cells were purified using protein G beads, and eluted fractions were analyzed by BLOOD, 20 APRIL 2017 x VOLUME 129, NUMBER 16 ANTILYMPHOMA ACTIVITY OF aCD20-IL- 21 FUSOKINE 2247 For personal use only. on March 28, 2019.…”

“…BLOOD, 20 APRIL 2017 x VOLUME 129, NUMBER 16 ANTILYMPHOMA ACTIVITY OF aCD20-IL- 21 FUSOKINE 2255 For personal use only. on March 28, 2019.…”

“…15 Combining mAbs with immunomodulatory molecules such as Toll-like receptor agonist (CpG ODN) or NK cell stimulatory NKG2D ligand or blocking Abs to NK cells' negative regulator (killer cell immunoglobulin-like receptor, KIR) have also shown promising results in preclinical studies. [16][17][18][19] Strategies combining mAbs with cytokines stimulating effector cells have also been attempted to enhance ADCC activity. 13,[20][21][22][23] Interleukin-21 (IL-21), a member of the IL-2 cytokine family, is a potent immunostimulatory cytokine exhibiting diverse regulatory effects on NK, T, and B cells.…”