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

Yadav, Preeti; McLeod, Victoria M.; Nowell, Cameron J.; Selby, Laura I.; Johnston, Angus P. R.; Kaminskas, Lisa M.; Trevaskis, Natalie L.

doi:10.1016/j.jconrel.2017.12.031

Cited by 16 publications

(13 citation statements)

References 29 publications

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“…HDL was not investigated in detail (25). Recently we reported that the mesenteric lymph, and to a lesser extent the hepatic lymph, are the main source of thoracic lymph fluid (57). This was confirmed in this study, and the lymph flow rates were comparable to previous reports from our laboratory and others (51,57).…”

Section: Discussionsupporting

confidence: 88%

“…The majority of lymph in the body converges at the thoracic lymph duct, including lymph from the mesentery, liver, lower limbs, and upper left region of the body. More than 80% of thoracic lymph flow has been reported to be contributed by mesenteric and hepatic lymph (34,57). As described above, the mesenteric lymph transports lipid-rich CM and VLDL secreted from the intestine (38).…”

Section: Introductionmentioning

confidence: 97%

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Organ-specific lymphatics play distinct roles in regulating HDL trafficking and composition

Gracia

Cao

Johnston

et al. 2020

American Journal of Physiology-Gastrointestinal and Liver Physi

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Recently, peripheral lymphatic vessels were found to transport high-density lipoprotein (HDL) from interstitial tissues to the blood circulation during reverse cholesterol transport. This function is thought to be critical to the clearance of cholesterol from atherosclerotic plaques. The role of organ-specific lymphatics in modulating HDL transport and composition is, however, incompletely understood. This study aimed to 1) determine the contribution of the lymphatics draining the intestine and liver (which are major sites of HDL synthesis) to total (thoracic) lymph HDL transport and 2) verify whether the HDLs in lymph are derived from specific organs and are modified during trafficking in lymph. The mesenteric, hepatic, or thoracic lymph duct was cannulated in nonfasted Sprague-Dawley rats, and lymph was collected over 5 h under anesthesia. Whole lymph and specific lymph lipoproteins (isolated by ultracentrifugation) were analyzed for protein and lipid composition. The majority of thoracic lymph fluid, protein, and lipid mass was sourced from the mesenteric, and to a lesser extent, hepatic lymph. Mesenteric and thoracic lymph were both rich in chylomicrons and very low-density lipoprotein, whereas hepatic lymph and plasma were HDL-rich. The protein and lipid mass in thoracic lymph HDL was mostly sourced from mesenteric lymph, whereas the cholesterol mass was equally sourced from mesenteric and hepatic lymph. HDLs were compositionally distinct across the lymph sources and plasma. The composition of HDL also appeared to be modified during passage from the mesenteric and hepatic to the thoracic lymph duct. Overall, this study demonstrates that the lipoproteins in lymph are organ specific in composition, and the intestine and liver appear to be the main source of HDL in the lymph. NEW & NOTEWORTHY High-density lipoprotein in lymph are organ-specific in composition and derive mostly from the intestine and liver. High-density lipoprotein also appears to be remodeled during transport through the lymphatics. These findings have implications to cardiometabolic diseases that involve perturbations in lipoprotein distribution and metabolism.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 97%

Organ-specific lymphatics play distinct roles in regulating HDL trafficking and composition

Gracia

Cao

Johnston

et al. 2020

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In benign LNs on the other hand, panitumumab-IRDye800CW signal is most likely the result of non-specific accumulation, as demonstrated by the dose-dependent increase in fluorescent antibody-complex detection in the lymphatic sinuses despite the absence of EGFR expression in those LNs. This hypothesis is further supported by studies of anti-human epidermal growth factor receptor-2 (HER2) receptor monoclonal antibody (trastuzumab) which can extravasate and circulate through the lymphatic system after intravenous injection 23,24 .…”

Section: Discussionmentioning

confidence: 89%

Optical molecular imaging can differentiate metastatic from benign lymph nodes in head and neck cancer

et al. 2019

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Identification of lymph node (LN) metastasis is essential for staging of solid tumors, and as a result, surgeons focus on harvesting significant numbers of LNs during ablative procedures for pathological evaluation. Isolating those LNs most likely to harbor metastatic disease can allow for a more rigorous evaluation of fewer LNs. Here we evaluate the impact of a systemically injected, near-infrared fluorescently-labeled, tumor-targeting contrast agent, panitumumab-IRDye800CW, to facilitate the identification of metastatic LNs in the ex vivo setting for head and neck cancer patients. Molecular imaging demonstrates a significantly higher mean fluorescence signal in metastatic LNs compared to benign LNs in head and neck cancer patients undergoing an elective neck dissection. Molecular imaging to preselect at-risk LNs may thus allow a more rigorous examination of LNs and subsequently lead to improved prognostication than regular neck dissection.

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“…Once a drug enters into systemic circulation by absorption or direct administration, it must be distributed into different organs or tissues [23] and its metabolites need to be removed from the body via excretion through the kidneys (urine) or the feces [24]. Although there are differences between small molecules and monoclonal antibodies, mAbs also can arrive at different tissues by convection.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Elucidation of Recombinant Humanized Anti-PD-1 Monoclonal Antibody (TA1718-B) Pharmacokinetics in Cynomolgus Monkeys, Rats, and Colon Cancer Humanized Mice

Zhao¹,

Lv²,

Li³

et al. 2019

Preprint

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[EXSCINDED] Abstract Background PD-1 monoclonal antibodies (mAbs) are widely applicated in clinical as therapeutic strategy for multiple types of cancer. TA1718-B, a novel PD-1 mAb, is now entering clinical phase I.Methods In present study, the preclinical pharmacokinetic (PK) properties of TA1718-B were investigatedviavarious experiments in animal species. In plasma kinetic studies, cynomolgus monkeys underwent either single (1, 3, and 10 mg/kg) or repeat (4-times, 3 mg/kg) intravenous injection and plasma were collected in different time points and detected by ELISA. Tissue distributions were performed in MC38 colon cancer humanizedmice. The excretion of TA1718-B was evaluated in rats.Results TA1718-B exhibited long T1/2 (from 97 to 136 hrs) and low clearance (Cl) (from 0.25 to 0.38 ml/h/kg) after intravenous single injection in cynomolgus monkeys. And 4-time continuous injections were not resulted in significant drug accumulation. However, both two drug delivery ways resulted in high anti-drug antibody (ADA) positive rates. The tissue distributions of TA1718-B were widely (almost in all tissues) and higher in serum, ovary, lung, tumorthan the other tissues in MC38 colon cancer humanized mice. The excretion of TA1718-B in rats were mainly metabolized and eliminated through proteolytic degradation.Radiopharmaceuticals in urine mainly existed in the form of proteolytic degradationfrom the data.Conclusion This systematic investigation of pharmacokinetic profiles of TA1718-B supplies basis for clinical trials and need to be further studied in Phase I clinical trial.

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

Cited by 16 publications

References 29 publications

Organ-specific lymphatics play distinct roles in regulating HDL trafficking and composition

Organ-specific lymphatics play distinct roles in regulating HDL trafficking and composition

Optical molecular imaging can differentiate metastatic from benign lymph nodes in head and neck cancer

Preclinical Elucidation of Recombinant Humanized Anti-PD-1 Monoclonal Antibody (TA1718-B) Pharmacokinetics in Cynomolgus Monkeys, Rats, and Colon Cancer Humanized Mice

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