Preeti Yadav, Victoria M McLeod, Lisa M. Kaminskas and Natalie L Trevaskis*

 

381 Royal Parade, Parkville 3052
Monash Institute of Pharmaceutical Sciences, Monash University,
Melbourne, VIC, Australia

 

The lymphatic system is a primary site for cancer metastatic spread, proliferation of infectious diseases and the response to inflammatory diseases. These conditions have in the past been treated with small molecule drugs that display limited lymphatic affinity, which in turn can restrict therapeutic efficacy1. Therapeutic proteins can better target and treat lymphatic diseases since they are cleared via the lymphatics following interstitial (SC or IM) delivery1-3. However, therapeutic proteins are often administered intravenously (IV). Recently therapeutic proteins have been found to access the lymph in high quantities after IV administration2-3. This study aimed to determine, for the first time, the major site/s of lymph access of biotherapeutics, and the protein properties that enhance lymph access, after IV administration. Novel methods were developed or optimised to collect hepatic, mesenteric or thoracic lymph from rats. Four different sized therapeutic proteins (native interferon α2b (IFN, 19kDa), PEGylated interferon α2b (IFN-PEG12, 31kDa), PEGylated interferon α2a (IFN-PEG40, 60 kDa) or trastuzumab (150 kDa)) were administered via short IV infusion, and plasma and lymph therapeutic concentrations determined by ELISA. Recovery in the thoracic lymph, which collects lymph from most of the body, was significantly greater for trastuzumab, IFN-PEG40 and IFN-PEG12 (all >3% dose over 8 h) when compared to native IFN (0.9% dose). Conversely, the thoracic lymph/plasma (L/P) concentration ratio and thus efficiency of extravasation and access to lymph was highest for the smaller proteins IFN and IFN-PEG12 (90-100% vs 15-30%). The lower lymph recovery of IFN and IFN-PEG12 was due to higher systemic clearance. For all proteins, >80% of lymph access occurred via the hepatic and mesenteric lymphatics due to the high lymph flow rates and enhanced extravasation across the fenestrated and sinusoidal blood capillaries. Optimising the properties of IV administered biotherapeutics (size, systemic clearance etc) represents a viable approach to target and treat lymphatic diseases, particularly in the liver and mesentery. Successful development of the novel technique to collect hepatic lymph will enable future work to evaluate tissue-specific lymph transport in health and disease.

Figure 1: Schematic representation of therapeutic protein transfer from the blood circulation through to lymph

1Trevaskis et al, Nat. Rev. Drug. Discov. 2015, 14, 781-803

2Kaminskas et al, J. Control. Release, 2013, 168, 200-208

3Dahlberg et al, Mol. Pharm., 2014, 11, 496-504

 

Biographic Details

Dr Natalie L Trevaskis

Affiliation, Country: Monash University, Australia

Phone: +613 9903 9708  E-mail: natalie.trevaskis@monash.edu

Research interests: lymphatic biology, drug delivery, biopharmaceutics, inflammatory diseases