The macroscopic and microscopic pharmacology of monoclonal antibodies

Weinstein, John N.; Osdol, William van

doi:10.1016/0192-0561(92)90176-l

Cited by 34 publications

(28 citation statements)

References 14 publications

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“…The capillary endothelium and the underlying basement membrane structure in brain are composed of tight-junction capillaries, and their intracellular junctions are closed by a belt of tight junctions (21,23). Under the conditions where the integrity of bloodbrain barrier (BBB) is intact, the presence of tight junctions prevents the transcellular route for diffusion of antibodies across the capillary.…”

Section: Biodistribution Of Marketed Antibodiesmentioning

confidence: 99%

“…In general, there are four types of blood capillaries that could facilitate the vascular transport of macromolecules such as IgG monoclonal antibodies (21). First, the continuous capillaries are distributed in structures such as connective tissue, skin, muscle, and a variety of other tissues throughout the body.…”

Section: General Biodistribution Mechanismsmentioning

confidence: 99%

“…Diffusion of large molecular weight substances such as dextran and IgG (both 150 kDa) in normal tissues was reported using an in vivo rabbit model (20,22). Finally, in brain, the capillary endothelium and the underlying basement membrane structure are composed of tight-junction capillaries, and their intracellular junctions are closed by a belt of tight junctions (21,23).…”

Section: General Biodistribution Mechanismsmentioning

confidence: 99%

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Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Tabrizi

Bornstein

Suria

2009

AAPS J

267

185

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Abstract. The monoclonal antibody market continues to witness an impressive rate of growth and has become the leading source of expansion in the biologic segment within the pharmaceutical industry. Currently marketed monoclonal antibodies target a diverse array of antigens. These antigens are distributed in a variety of tissues such as tumors, lungs, synovial fluid, psoriatic plaques, and lymph nodes. As the concentration of drug at the proximity of the biological receptor determines the magnitude of the observed pharmacological responses, a significant consideration in effective therapeutic application of monoclonal antibodies is a thorough understanding of the processes that regulate antibody biodistribution. Monoclonal antibody distribution is affected by factors such as molecular weight, blood flow, tissue and tumor heterogeneity, structure and porosity, target antigen density, turnover rate, and the target antigen expression profile.

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Section: Biodistribution Of Marketed Antibodiesmentioning

confidence: 99%

Section: General Biodistribution Mechanismsmentioning

confidence: 99%

Section: General Biodistribution Mechanismsmentioning

confidence: 99%

See 1 more Smart Citation

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Tabrizi

Bornstein

Suria

2009

AAPS J

267

185

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show abstract

“…to detect or treat a solid tumor, they generally distribute nonuniformly in the mass (1)(2)(3)(4)(5)(6)(7)(8). A number of possible reasons, reflecting the heterogeneity seen in almost all characteristics of cancer (9)(10)(11), have been suggested: heterogeneous antigen (Ag) expression within the tumor; heterogeneous blood supply; elevated interstitial pressure; and mechanical barrierse.g., tight junctions between cells (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

mentioning

confidence: 99%

Targeting cancer micrometastases with monoclonal antibodies: a binding-site barrier.

Saga

Neumann

Heya

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

164

103

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Monoclonal antibodies penetrate bulky tumors poorly after intravenous administration, in part because of specific binding to the target antigen. Experiments presented here demonstrate an analogous phenomenon in micrometastases; poor antibody penetration, attributable to a "binding-site barrier" phenomenon, can be seen in guinea pig micrometastases as small as 300 ,um in diameter. Increasing the dose of antibody can partially overcome this limitation, but at a cost in specificity. Six and 72 hr after injection, animals were sacrificed by CO2 inhalation. Organs were rapidly removed and weighed, and tissue radioactivity was determined. Lung tissues with metastases were frozen immediately in OCT compound (Tissue-Tek, Miles) and then processed for autoradiography and immunostaining. For high-dose experiments, 1000 ,ug of unlabeled D3 was added to 30 ,ug of labeled D3. Autoradiography and Immunostaining. Serial 20-,um sections were cut from the frozen lung tissues. For autoradiography, sections were placed on SB-5 film (Eastman Kodak) and exposed for 1-4 days. When 125I-labeled BL3 was coinjected with I311-labeled D3, images of the latter were obtained shortly after sacrifice, images of the former after eight 131I half-lives.The avidin-biotin peroxidase complex (ABC) method (29) was used to compare Ab and Ag distribution. Briefly, tissue sections were acetone-fixed for 10 min and incubated with blocking serum for 20 min. To assess Ag expression, sections were incubated with D3 Ab (20 ,ug/ml) for 1 hr at room temperature, biotinylated horse anti-mouse IgG for 45 min, ABC for three 30-min periods, and diaminobenzidine (Vector Laboratories). When injected D3 was assessed, incubation with D3 was omitted. Some sections were also stained for blood vessels by use of polyclonal rabbit anti-factor VIII and an alkaline phosphatase substrate, Vector Red (30). RESULTS AND DISCUSSIONIn this study, we have assessed the distribution of i.v. administered mAbs in experimental guinea pig lung micrometastases. Two weeks after i.v. injection of L10 cells, multiple metastases 100-1000 ,um in diameter could be seen in the lungs of all animals. This model (metastasis of guinea pig cancer in guinea pigs) is in many ways more relevant to the Abbreviations: Ab, antibody; mAb, monoclonal Ab; Ag, antigen.

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“…MAbs can freely travel through the large (~100 nm) sinusoidal clefts in the liver 29 and thus readily access target proteins on the hepatocyte cell surface. We used a serial design and evaluated K21 distribution in the liver at several time points by measuring K21 level in the tissue and in the serum by ELISA and by immunostaining of K21 bound to hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Target-mediated drug disposition and prolonged liver accumulation of a novel humanized anti-CD81 monoclonal antibody in cynomolgus monkeys

Vexler¹,

Yu²,

Pamulapati³

et al. 2013

mAbs

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The macroscopic and microscopic pharmacology of monoclonal antibodies

Cited by 34 publications

References 14 publications

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Targeting cancer micrometastases with monoclonal antibodies: a binding-site barrier.

Target-mediated drug disposition and prolonged liver accumulation of a novel humanized anti-CD81 monoclonal antibody in cynomolgus monkeys

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