Distribution of therapeutic proteins into thoracic lymph after intravenous administration is protein size-dependent and primarily occurs within the liver and mesentery

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Abstract

Therapeutic proteins can facilitate the targeting and treatment of lymphatic diseases (such as cancer metastases, infections and inflammatory diseases) since they are cleared via the lymphatics following interstitial (SC or IM) administration. However, therapeutic proteins are often administered intravenously (IV). Recently therapeutic proteins have been found to access the thoracic lymph in surprisingly high quantities after IV administration. The aim of this study was to determine, for the first time, the major sites of thoracic lymph access of therapeutic proteins, and the protein properties that enhance lymph access, after IV administration.

In order to achieve this, novel methods were developed or optimized to collect hepatic, mesenteric or thoracic lymph from male SD rats. Four different sized PEGylated or non-PEGylated therapeutic proteins (native interferon α2b (IFN, 19 kDa), PEGylated interferon α2b (IFN-PEG12, 31 kDa), PEGylated interferon α2a (IFN-PEG40, 60 kDa) or trastuzumab (150 kDa)) were then administered via short IV infusion, and plasma and lymph concentrations of the proteins determined via ELISA.

The recovery of the therapeutic proteins in the thoracic lymph duct, 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 transport through the interstitium to lymph was highest for the smaller proteins IFN and IFN-PEG12 (at 90–100% vs 15–30% for trastuzumab and IFN-PEG40). The lower total recovery of IFN and IFN-PEG12 in thoracic lymph reflected more rapid systemic clearance and thus lower systemic exposure. For all therapeutic proteins, the majority (> 80%) of lymph access occurred via the hepatic and mesenteric lymphatics. This lymphatic distribution pattern was supported by quantitative imaging of the lymph node distribution of IV administered Cy5 labelled trastuzumab.

Optimizing the properties of IV administered therapeutic proteins represents a viable approach to better target and treat pathological states involving the lymphatics, particularly in the liver and mesentery. This includes cancer metastases, infections and inflammatory diseases. Successful development of the novel technique to collect hepatic lymph will also enable future work to evaluate tissue-specific lymph transport in health and disease.

Graphical abstract

Schematic representation of the extravasation and transfer of therapeutic proteins (large vs small sizes represented by black vs blue circles, respectively) from the blood circulation through to lymph. Therapeutic proteins predominantly transfer from blood to lymph within liver and mesentery/intestine (i.e. viscera). This is because of the high lymph flow rates from these areas as well as the enhanced extravasation of proteins across the fenestrated and sinusoidal blood capillaries of the mesentery and liver. Optimizing the properties of IV administered therapeutic proteins represents a viable approach to better target and treat pathological states involving the visceral lymphatics such as cancers, inflammatory diseases and infection. Note: the picture of the human body is adapted from http://www.xtend-life.com.

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