A single-domain bispecific antibody targeting CD1d and the NKT T-cell receptor induces a potent anti-tumor response

The type 1 NKT cell stimulating glycolipid α-galactosylceramide (α-GalCer) was first identified by the Pharmaceutical Research Laboratory of Kirin Brewery in a screen for novel anti-tumor agents. Based on promising preclinical data it was tested as an anticancer drug in multiple clinical studies.

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 While anti-tumor activity was noted in several studies results were not consistent and robust enough for broad clinical use. In an effort to generate novel therapeutic tools we generated a panel of lama-derived single domain antibodies (VHHs) specific for CD1d, a monomorphic molecule not only critical for presentation of α-GalCer to type 1 NKT cells but also for the activity of other CD1d-restricted T cell subsets including (protumor) type 2 NKT cells.

In our recently published paper in Nature Cancer we report that distinct CD1d specific VHHs can selectively block the activity of individual CD1d- restricted T cell subsets and identified VHH1D12 to be particularly unique as it combined blocking of type 2 NKT cell activation with the potent induction of type 1 NKT cell activation, the latter even in the absence of normally required exogenous glycolipid antigens such as α-GalCer. Using crystallography co-first authors Roeland Lameris and Adam Shahine elucidated that VHH1D12 simultaneously contacted CD1d and the type 1 NKT TCR and thereby stabilized this interaction through intrinsic bispecificity (see Figure). VHH1D12 not only outperformed α-GalCer in multiple assays but may also trigger more tumor specific activity as it especially promoted type 1 NKT cell reactivity when CD1d contained (endogenous) low-affinity glycolipid antigens that are common in cancer cells. The unique features of CD1d specific VHHs that we describe have the potential to advance NKT cell based therapies and provide a first example of what may develop into a more broadly applicable novel cancer immunotherapy approach.

Jamie Rossjohn

Professor, Monash University

Professor Jamie Rossjohn’s research is centered on an understanding immunity. He is currently an ARC Australian Laureate Fellow (2017-2021) and previously a NHMRC Australia Fellow (2011-2016) and ARC Federation Fellow (2007-11). Prof. Rossjohn is known for his contributions to the understanding the molecular basis underpinning immunity. He has used structural biology to explain pre-T- cell receptor (TCR) self-association in T-cell development, and how the TCR specifically recognises polymorphic Human Leukocyte Antigen (HLA) molecules in the context of viral immunity and aberrant T- cell reactivity. He has unearthed structural mechanisms of HLA polymorphism impacting on drug and food hypersensitivities, as well as Natural Killer cell receptor recognition. He has pioneered our molecular understanding of lipid-based immunity by T cells, revealing that it can differ fundamentally from peptide-mediated adaptive immunity. Recently he has provided a structural basis of how vitamin B metabolites can be presented and recognised by the immune system, revealing a new class of antigen. Collectively, he has published > 400 papers and mentored numerous researchers towards obtaining higher degrees and nationally competitive fellowships.