cancer antibody that targets the innate immune system

StephenW

这对乙肝病毒感染有效吗?

http://www.nature.com/nrd/journal/v10/n9/full/nrd3537.html?WT.ec_id=BIOPHARMA-20111005

Biobusiness Briefs: Deal watch:  Bristol-Myers Squibb invests in cancer antibody that targets the innate immune system

Bristol-Myers Squibb has acquired exclusive global rights to Innate Pharma's cancer candidate IPH 2102, which is in Phase I clinical trials for acute myeloid leukaemia (AML). Innate Pharma will receive US$35 million upfront and is eligible to receive up to $430 million in milestones.

IPH 2102 is a fully human monoclonal antibody that blocks the interaction between killer cell immunoglobulin-like receptors (KIRs) on natural killer (NK) cells and their ligands. NK cells are white blood lymphocytes of the innate immune system and are our first line of defence against pathogens or host cells that are stressed and/or cancerous. As Dr Jerry Thornthwaite (Director, Cancer Research Institute of West Tennessee, USA) explains: “All normal cells bear a self recognition protein called major histocompatability complex I (MHCI). NK cells recognize the MHCI by their KIRs and this interaction shuts down the ability of the NK cells to kill these cells. If a cell does not contain an MHCI or presents an altered MHCI — as in viral, infected or cancer cells — the NK cell will release proteins that will lyse and kill target cells.”

By blocking KIRs with agents such as IPH 2102, NK cell activation is facilitated and so is their ability to destroy tumour cells. Moreover, “theoretically enhanced NK cell activity may suppress metastases, the greatest killer of patients with cancer”, adds Dr Mark Smyth (Peter MacCallum Cancer Institute, Melbourne, Australia).

Velardi and colleagues (Science 295, 2097–2100; 2002) were the first to show that patients with AML benefited from NK cell alloreactivity during haematopoietic transplantation therapies. “Specifically, a lack of appropriate MHCI ligand for inhibitory KIRs resulted in loss of tolerance towards the recipient's cells, including the tumour. Based on these findings, it has become clear that disrupting inhibitory KIR function can tip the activation balance of NK cells from tolerant sentinels to enhanced tumour cell killers,” says Kerry Campbell (Associate Professor, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA).

How are these activated NK cells prevented from harming healthy cells? It has been shown that “additional tolerance mechanisms are in place in NK cells that prevent unrestricted attack until an activating receptor is also specifically engaged with the target cell, thereby providing a further safety mechanism to prevent the destruction of normal cells”, explains Campbell. “This suggests that KIR blockade alone will not break tolerance of NK cells towards normal cells and unleash a generalized autoimmune response,” he adds.

Compared to cancer immunotherapies that target the adaptive immune response, “the main advantage of agents such as IPH 2102 is that they are targeting the earliest immune reaction to tumours and this could be most useful for the treatment of haematological cancers like AML and multiple myeloma”, comments Smyth. Furthermore, he concludes that: “NK cells may participate in antibody-dependent cellular cytotoxicity (ADCC), and thus co-administering IPH 2102 with other anticancer antibodies that mediate ADCC, such as rituximab, may potentiate their activity.”

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