Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR) signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course.

The c-Jun N-terminal kinase (JNK) signaling pathway is essential for neuronal degeneration in multiple contexts but also regulates neuronal homeostasis. It remains unclear how neurons are able to dissociate proapoptotic JNK signaling from physiological JNK activity. In this paper, we show that the mixed lineage kinase dual leucine zipper kinase (DLK) selectively regulates the JNK-based stress response pathway to mediate axon degeneration and neuronal apoptosis without influencing other aspects of JNK signaling. This specificity is dependent on interaction of DLK with the scaffolding protein JIP3 to form a specialized JNK signaling complex. Local activation of DLK-based signaling in the axon results in phosphorylation of c-Jun and apoptosis after redistribution of JNK to the cell body. In contrast, regulation of axon degeneration by DLK is c-Jun independent and mediated by distinct JNK substrates. DLK-null mice displayed reduced apoptosis in multiple neuronal populations during development, demonstrating that prodegenerative DLK signaling is required in vivo.

After a decade of research on immunological approaches to treating Alzheimer's disease (AD), much has been learned about selection criteria for antibodies targeting β-amyloid (Abeta). Here we describe the preclinical properties of an anti-Abeta MAb, MABT5102A, which has been selected for testing as a disease modifying therapeutic in patients with AD. Monoclonal antibodies (MAbs) were generated by immunization of mice with pegylated Abeta peptide integrated into liposomes. Murine anti-Abeta MAbs were further characterized using both in vitro and in vivo methods to evaluate Abeta binding and toxicity. An anti-Abeta MAb was then selected for humanization and affinity maturation and further evaluated in vitro and in PKPD models. A parental murine MAb was selected that bound to multiple forms of Abeta. Treatment with this MAb showed an increase in cognitive memory capacity in an animal model of AD (hAPP-Tg). Long-term dosing studies with this MAb in an aged AD mouse model resulted in a reduction in plaque load and number. This murine MAb was affinity matured and humanized to give rise to MABT5102A. In vitro, MABT5102A bound equally well and with high affinity to monomer-, oligomer- and fiber-enriched preparations of Abeta1-42 peptide. Furthermore, binding of MABT5102A inhibited self-association and aggregation of Abeta peptides into protofibrillar conformations, and it disaggregated pre-formed Abeta1-42 protofibrils. MABT5102A also blocked Abeta oligomer-induced toxicity on primary neurons. In vivo PKPD and safety studies with MABT5102A supported initiation of phase I clinical trials. A humanized monoclonal antibody, MABT5102A, was selected based on various desirable in vitro and in vivo properties and is currently in a phase I clinical study enrolling mild to moderate AD patients.