A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma.

In this open-label, multicentre, phase 1 study a fully human anti-CD40 antagonist monoclonal antibody, lucatumumab, was evaluated in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to determine the maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs). Secondary objectives included safety, pharmacokinetics, pharmacodynamics and antimyeloma activity. Twenty-eight patients, enrolled using a standard '3 + 3' dose escalation, received one or two (n = 3) cycles of lucatumumab 1·0, 3·0, 4·5 or 6·0 mg/kg once weekly for 4 weeks. Common lucatumumab-related adverse events were reversible, mild-to-moderate infusion reactions. Severe adverse events were anaemia, chills, hypercalcaemia and pyrexia (7% each). DLTs included grade 4 thrombocytopenia, grade 3 increased alanine aminotransferase and grade 4 increased lipase (n = 1 each). The MTD was 4·5 mg/kg. At doses ≥3·0 mg/kg, sustained receptor occupancy (≥87%), observed throughout weekly infusions up to 5 weeks after the last infusion, correlated with an estimated half-life of 4-19 d. Twelve patients (43%) had stable disease, and one patient (4%) maintained a partial response for ≥8 months. These findings indicate that single-agent lucatumumab was well tolerated up to 4·5 mg/kg with modest clinical activity in relapsed/refractory MM, warranting further study as a combination therapy.

Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia.

Lucatumumab is a fully humanized anti-CD40 antibody that blocks interaction of CD40L with CD40 and also mediates antibody-dependent cell-mediated cytotoxicity (ADCC). We evaluated lucatumumab in a phase I clinical trial in chronic lymphocytic leukemia (CLL). Twenty-six patients with relapsed CLL were enrolled on five different dose cohorts administered weekly for 4 weeks. The maximally tolerated dose (MTD) of lucatumumab was 3.0 mg/kg. Four patients at doses of 4.5 mg/kg and 6.0 mg/kg experienced grade 3 or 4 asymptomatic elevated amylase and lipase levels. Of the 26 patients enrolled, 17 patients had stable disease (mean duration of 76 days, range 29-504 days) and one patient had a nodular partial response for 230 days. Saturation of CD40 receptor on CLL cells was uniform at all doses post-treatment but also persisted at trough time points in the 3.0 mg/kg or greater cohorts. At the MTD, the median half-life of lucatumumab was 50 h following the first infusion, and 124 h following the fourth infusion. In summary, lucatumumab had acceptable tolerability, pharmacokinetics that supported chronic dosing and pharmacodynamic target antagonism at doses of 3.0 mg/kg, but demonstrated minimal single-agent activity. Future efforts with lucatumumab in CLL should focus on combination-based therapy.

Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products.

The multiligand receptor for advanced glycation end products (RAGE) mediates certain chronic vascular and neurologic degenerative diseases accompanied by low-grade inflammation. RAGE ligands include S100/calgranulins, a class of low-molecular-mass, calcium-binding polypeptides, several of which are chondrocyte expressed. Here, we tested the hypothesis that S100A11 and RAGE signaling modulate osteoarthritis (OA) pathogenesis by regulating a shift in chondrocyte differentiation to hypertrophy. We analyzed human cartilages and cultured human articular chondrocytes, and used recombinant human S100A11, soluble RAGE, and previously characterized RAGE-specific blocking Abs. Normal human knee cartilages demonstrated constitutive RAGE and S100A11 expression, and RAGE and S100A11 expression were up-regulated in OA cartilages studied by immunohistochemistry. CXCL8 and TNF-alpha induced S100A11 expression and release in cultured chondrocytes. Moreover, S100A11 induced cell size increase and expression of type X collagen consistent with chondrocyte hypertrophy in vitro. CXCL8-induced, IL-8-induced, and TNF-alpha-induced but not retinoic acid-induced chondrocyte hypertrophy were suppressed by treatment with soluble RAGE or RAGE-specific blocking Abs. Last, via transfection of dominant-negative RAGE and dominant-negative MAPK kinase 3, we demonstrated that S100A11-induced chondrocyte type X collagen expression was dependent on RAGE-mediated p38 MAPK pathway activation. We conclude that up-regulated chondrocyte expression of the RAGE ligand S100A11 in OA cartilage, and RAGE signaling through the p38 MAPK pathway, promote inflammation-associated chondrocyte hypertrophy. RAGE signaling thereby has the potential to contribute to the progression of OA.

The 3rd International Meeting on Gene Therapy in Rheumatology and Orthopaedics.

The 3rd International Meeting on Gene Therapy in Rheumatology and Orthopaedics was held in Boston, Massachusetts, USA in May 2004. Keystone lectures delivered by Drs Joseph Glorioso and Inder Verma provided comprehensive, up-to-date information on all major virus vectors. Other invited speakers covered the application of gene therapy to treatment of arthritis, including the latest clinical trial in rheumatoid arthritis, as well as lupus and Sjögren's syndrome. Applications in mesenchymal stem cell biology, tissue repair, and regenerative medicine were also addressed. The field has advanced considerably since the previous meeting in this series, and further clinical trials seem likely.

Pain related behaviour in two models of osteoarthritis in the rat knee.

Osteoarthritis (OA) is a major healthcare burden, with increasing incidence. Pain is the predominant clinical feature, yet therapy is ineffective for many patients. While there are considerable insights into the mechanisms underlying tissue remodelling, there is poor understanding of the link between disease pathology and pain. This is in part owing to the lack of animal models that combine both osteoarthritic tissue remodelling and pain. Here, we provide an analysis of pain related behaviours in two models of OA in the rat: partial medial meniscectomy and iodoacetate injection. Histological studies demonstrated that in both models, progressive osteoarthritic joint pathology developed over the course of the next 28 days. In the ipsilateral hind limb in both models, changes in the percentage bodyweight borne were small, whereas marked mechanical hyperalgesia and tactile allodynia were seen. The responses in the iodoacetate treated animals were generally more robust, and these animals were tested for pharmacological reversal of pain related behaviour. Morphine was able to attenuate hyperalgesia 3, 14 and 28 days after OA induction, and reversed allodynia at days 14 and 28, providing evidence that this behaviour was pain related. Diclofenac and paracetamol were effective 3 days after arthritic induction only, coinciding with a measurable swelling of the knee. Gabapentin varied in its ability to reverse both hyperalgesia and allodynia. The iodoacetate model provides a basis for studies on the mechanisms of pain in OA, and for development of novel therapeutic analgesics.