Interstitial exclusion of IgG in rat tissues estimated by continuous infusion

Wiig, Helge; Kaysen, George A.; Al-Bander, Hamoudi; Carlo, M. De; Sibley, L.; Renkin, Eugene M.

doi:10.1152/ajpheart.1994.266.1.h212

Cited by 27 publications

(43 citation statements)

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“…Our observation that such treatment did not improve the transport of antibody correlates with the finding that the space available to IgG in these tumors is quite large compared with normal muscle (11). The interstitial space available to IgG is thus unlikely to be the limiting factor for antibody transport so a further increase in this space after hyaluronidase treatment does not result in an enhancement of antibody transport.…”

Section: Discussionsupporting

confidence: 78%

Intraperitoneal Immunotherapy for Metastatic Ovarian Carcinoma: Resistance of Intratumoral Collagen to Antibody Penetration

Choi¹,

Credit²,

Henderson³

et al. 2006

Clinical Cancer Research

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Purpose: Convective transport of macromolecules from the peritoneal cavity into tumor is determined by its hydraulic permeability and the pressure gradient. Previous studies showed that establishing a pressure gradient into the tumor failed to result in significant penetration. This study addresses the hypothesis that the extracellular matrix is the major resistance to the penetration of an i.p. injected antibody. Experimental Design: Human ovarian tumors (SKOV-3 and OVCAR-3) were established in the abdominal wall of athymic rats. After anesthesia, the tumor serosal surface was treated for 2 hours with Krebs solution (control), collagenase (37.5 unit/mL), or hyaluronidase (10 unit/mL) followed by 3 hours of convective delivery of radiolabeled IgG. Transport of antibody into the tumor was measured with quantitative autoradiography along with the tumor interstitial pressure, concentration of collagen and hyaluronic acid, and IgG volume of distribution. Results: Antibody was excluded from 42% to 53% of tumor extracellular volume. Exposure of tumors to hyaluronidase did not enhance IgG transport despite removal of 90% of the hyaluronan from the exposed tumor. In contrast, collagenase reduced collagen content, lowered tumor interstitial pressure, and markedly enhanced antibody penetration. Conclusions: Reduction of collagen, but not hyaluronan, in the matrix of ovarian xenografts enhanced the transport of i.p. injected antibody. Although high interstitial pressure is a deterrent to convective transport of macromolecules into the tumor parenchyma, the structure of the interstitial matrix provides an inherent resistance, which must be overcome before effective delivery of an antibody.

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Section: Discussionsupporting

confidence: 78%

Intraperitoneal Immunotherapy for Metastatic Ovarian Carcinoma: Resistance of Intratumoral Collagen to Antibody Penetration

Choi¹,

Credit²,

Henderson³

et al. 2006

Clinical Cancer Research

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“…This study showed that the corrected tissue concentration in muscle and skin exceeds that of plasma after 72 h for both ABD-(Z HER2:342 ) 2 and RSA, equal to the time to reach steady state using continuous infusion of RSA (72 h) (51). This is faster than what has been determined with infusion of IgG (120 h) (52). Thus, if IgG and ABD-(Z HER2:342 ) 2 were labeled with the same isotope, ABD-(Z HER2:342 ) 2 would reach steady state earlier, suggesting a more rapid accumulation of radioactivity in tissues and metastases.…”

Section: Discussionmentioning

confidence: 60%

Extending Half-life by Indirect Targeting of the Neonatal Fc Receptor (FcRn) Using a Minimal Albumin Binding Domain

Andersen

Pehrson

Tolmachev

et al. 2011

Journal of Biological Chemistry

150

115

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The therapeutic and diagnostic efficiency of engineered small proteins, peptides, and chemical drug candidates is hampered by short in vivo serum half-life. Thus, strategies to tailor their biodistribution and serum persistence are highly needed. An attractive approach is to take advantage of the exceptionally long circulation half-life of serum albumin or IgG, which is attributed to a pH-dependent interaction with the neonatal Fc receptor (FcRn) rescuing these proteins from intracellular degradation. Here, we present molecular evidence that a minimal albumin binding domain (ABD) derived from streptococcal protein G can be used for efficient half-life extension by indirect targeting of FcRn. We show that ABD, and ABD recombinantly fused to an Affibody molecule, in complex with albumin does not interfere with the strictly pH-dependent FcRn-albumin binding kinetics. The same result was obtained in the presence of IgG. An in vivo study performed in rat confirmed that the clinically relevant human epidermal growth factor 2 (HER2)-targeting Affibody molecule fused to ABD has a similar half-life and biodistribution profile as serum albumin. The proof-of-concept described may be broadly applicable to extend the in vivo half-life of short lived biological or chemical drugs ultimately resulting in enhanced therapeutic or diagnostic efficiency, a more favorable dosing regimen, and improved patient compliance.

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“…Hyaluronan molecules are highly negatively charged, imbibe large amounts of water, and restrict the passage of negatively charged proteins (36). The proteins are restricted to ϳ50% of interstitial space (111,112). This means, for example, that in muscle interstitial space, which is 12-20% of the total tissue space, only 6 -10% of that space will be for transport of largemolecular-mass proteins.…”

Section: Interstitial Matrixmentioning

confidence: 99%

The transport barrier in intraperitoneal therapy

Flessner

2005

American Journal of Physiology-Renal Physiology

202

171

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The peritoneal cavity is important in clinical medicine because of its use as a portal of entry for drugs utilized in regional chemotherapy and as a means of dialysis for anephric patients. The barrier between the therapeutic solution in the cavity and the plasma does not correspond to the classic semipermeable membrane but instead is a complex structure of cells, extracellular matrix, and blood microvessels in the surrounding tissue. New research on the nature of the capillary barrier and on the orderly array of extracellular matrix molecules has provided insights into the physiological basis of osmosis and the alterations in transport that result from infusion of large volumes of fluid. The anatomic peritoneum is highly permeable to water, small solutes, and proteins and therefore is not a physical barrier. However, the cells of the mesothelium play an essential role in the immune response in the cavity and produce cytokines and chemokines in response to contact with noncompatible solutions. The process of inflammation, which depends on the interaction of mesothelial, interstitial, and endothelial cells, ultimately leads to angiogenesis and fibrosis and the functional alteration of the barrier. New animal models, such as the transgenic mouse, will accelerate the discovery of methods to preserve the functional peritoneal barrier.

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Interstitial exclusion of IgG in rat tissues estimated by continuous infusion

Cited by 27 publications

References 0 publications

Intraperitoneal Immunotherapy for Metastatic Ovarian Carcinoma: Resistance of Intratumoral Collagen to Antibody Penetration

Intraperitoneal Immunotherapy for Metastatic Ovarian Carcinoma: Resistance of Intratumoral Collagen to Antibody Penetration

Extending Half-life by Indirect Targeting of the Neonatal Fc Receptor (FcRn) Using a Minimal Albumin Binding Domain

The transport barrier in intraperitoneal therapy

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