The predicted models for the structures and mode of hormone binding of the glycoprotein hormone receptors are to a large extent consistent with currently available biochemical and mutational data. Repeated sequences in beta-barrel proteins are shown to have general implications for constraints on structure. Averaging techniques used here to recognize the structural motif in these receptors should also apply to other proteins with repeated sequences.

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BACKGROUND: Advanced multiple myeloma (MM) and Waldenströ m's macroglobulinemia (WM) are incurable B-cell malignancies. This is the first full clinical report of atacicept, a fusion protein that binds to and neutralises the B-cell survival factors, B-lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL), in MM and WM. METHODS: In this open-label phase-I study, 16 patients with advanced disease (12 MM, 4 WM) received one cycle of five once-weekly subcutaneous injections of atacicept (2, 4, 7 or 10 mg kg À1 ). Patients with stable disease after cycle 1 entered an extension study (either two additional cycles (2, 4 and 7 mg kg À1 cohorts) or 15 consecutive weekly injections of atacicept 10 mg kg À1 ).

We have recently derived a series of cloned cell lines displaying natural killer (NK) cell-like activity from normal human fetal blood (25 weeks). The lines were obtained after repeated stimulation of mononuclear cells with allogeneic Epstein-Barr virus (EBV)-transformed B lymphocytes and are interleukin-2 (IL-2) dependent. Initial characterization of the clones has been reported previously. Certain of these clones have been found to have unusual surface characteristics, namely, they are recognized by several well-defined anti-T3 antibodies, but do not react with WT31, which is thought to recognise an invariant epitope of the human (Ti-alpha beta) structure. Transcription of the genes encoding the alpha- and beta-chains of the T-cell receptor was assessed in two of these clones (F6A4 and F6C7). Ti-beta genes were found to be expressed, whereas alpha messenger RNA was not detected in Northern blot analysis. These data strongly suggest that these cells do not produce a stoichiometric T3/Ti-alpha beta receptor complex. However, experiments performed with a monoclonal antibody (anti-NKFi) developed against F6C7 cells demonstrated the existence of a unique clonotypic structure [relative molecular mass (Mr) 85,000 (85K)] which is surface-associated with T3 proteins. Furthermore, both anti-T3 and anti-NKFi were found to block cytotoxic effector function. Together, the results support the view that T3 proteins are involved in non-major histocompatibility complex (MHC)-restricted cytotoxic reactions mediated by certain circulating fetal lymphocytes which are likely to use a clonotypic structure distinct from both the 'first' (alpha beta) and the putative 'second' (gamma delta) T-cell receptor to recognize their target. The present studies were designed to characterize this structure.