Synaptic loss and subsequent neuronal death are paramount pathology in neurodegeneration. Therapeutic interventions that restore or prevent such events hold promise as disease modifying therapies. Brain derived neurotrophic factor (BDNF) is the best known neurotrophin to strengthen synaptic plasticity and promote neuron survival via its cognate receptor TrkB. Due to druggability limitations, however, BDNF failed to demonstrate effective neuroprotection in the clinic. Development of agents that can activate TrkB efficaciously in vivo became an attractive therapeutic pursuit. 4B Tech has discovered a series of potent and selective TrkB agonistic mAbs (TrkB agoAbs), which bind/activate TrkB with superior pharmaceutical properties to BDNF. Unlike BDNF, the TrkB agoAbs’ action is highly specific with no detectable cross-reactivity with p75, a co-receptor of BDNF and the activation of which would cause detrimental effects. The therapeutic potential of TrkB agoAbs has been demonstrated in a wide range of preclinical disease models and is on the way to be validated in the clinic.  

Neuroinflammation is fundamental to most, if not all, neurodegenerative diseases whereas microglia, the chief brain resident immune cells, are a major component of neuroinflammatory process. Homeostatic microglia have immune surveillance function and are activated under the pathophysiological conditions in brain diseases.  Overactivation of microglia triggers chronic neuroinflammation, which leads to synaptic and neuronal degeneration. Therefore, modulation of microglia function is another approach to alleviate neuronal damages by inflammation and slow down disease progression. Microglia’s function and survival depend on CSF1R signaling pathway. A CSF1R antagonist would dampen neuroinflammation by regulating/normalizing overly activated microglia. 4B Tech is advancing its CSF1R antagonist into clinic for proof of concept in the treatment of amyotrophic lateral sclerosis and other CNS diseases.

Due to special features of the CNS such as non-regenerative neuronal loss, existence of blood-brain barrier (BBB), anatomical/neurochemical compartmentation and interconnectivity, and interspecies translatability etc, there are several unique challenges in developing CNS medicines.  As such, in addition to the right targets and drug molecules, development of enabling technologies is essential to ensure that drug development is conducted efficiently and effectively, and the therapeutic mechanisms are appropriately evaluated in the clinical POC studies.  4B Tech is, in collaboration with partners, developing a series of such technology enablers including animal models with human-like disease pathologies, cross-BBB drug delivery, clinical relevant biomarkers, and AI-aided measurements for precision patient stratification and efficacy evaluation in clinical trials. All in all, these efforts are to enhance the quality of program decision making and ultimately the overall probability of clinical success.