Affinity and Avidity in Antibody-Based Tumor Targeting

Rudnick, Stephen I.; Adams, Gregory P.

doi:10.1089/cbr.2009.0627

Cited by 202 publications

(179 citation statements)

References 34 publications

(52 reference statements)

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“…In addition to tumor properties (outlined in next section), penetration of antibodies into tumors can be influenced by factors such as antibody affinity, antigen internalization, and antibody metabolism by the tumor. A number of comprehensive reviews have recently addressed this topic in detail (44)(45)(46)(47). Under nonsteady-state conditions, an inverse relationship between antibody affinity and tumor penetration has been predicted (48).…”

Section: Impact Of Affinity On Antibody Elimination and Distributionmentioning

confidence: 99%

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: Impact Of Affinity On Antibody Elimination and Distributionmentioning

confidence: 99%

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Tabrizi

Bornstein

Suria

2009

AAPS J

267

185

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show abstract

“…Although such an exosite still awaits experimental confirmation, it is of note that a similar bi/multivalency is well known to increase the affinity/'avidity' and long-lasting binding of antibodies and of many other biological interactions [56]. This concept is well established in biological therapeutics and is increasingly relied upon to generate highly effective drugs and tracers [57][58][59][60]. An essential feature of the current models …”

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confidence: 99%

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future. IntroductionThe pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug are determinants of its efficacy and the duration of its clinical action [1]. PK and PD have long been considered to be separate disciplines, and the time course of the pharmacological effect of a drug has essentially been considered in terms of the temporal fluctuation of its free concentration [2]. In accordance with this principle, the frequently observed time lag between the concentration of a drug in the systemic circulation and its effect was initially attributed to slow equilibration between the plasma and a hypothetical target-surrounding 'effect compartment' [3]. By contrast, preclinical screening studies traditionally aim to optimize drug candidates in terms of only their efficacy and potency (i.e. PD properties). Inherent to this practice is the proposal that drug-target interactions are adequately described by equilibrium equations and, hence, that association and dissociation rates play only subordinate roles. In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al. [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times. This property is now recognized to play a key role with respect to the clinical British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016...

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“…Previous studies suggested that the binding affinity for antigen plays a pivotal role in the total concentration and penetration of scFv into tumors (13,14). On the basis of scFv/rGel immunotoxins, we showed that increasing affinity could improve cell-binding ability, internalization efficiency, and autophagic cytotoxicity on Her2/neu-positive cells.…”

Section: Discussionmentioning

confidence: 66%

Single-Chain Antibody-Based Immunotoxins Targeting Her2/neu: Design Optimization and Impact of Affinity on Antitumor Efficacy and Off-Target Toxicity

Cao

Marks

Huang

et al. 2012

Molecular Cancer Therapeutics

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Recombinant immunotoxins, consisting of single-chain variable fragments (scFv) genetically fused to polypeptide toxins, represent potentially effective candidates for cancer therapeutics. We evaluated the affinity of various anti-Her2/neu scFv fused to recombinant gelonin (rGel) and its effect on antitumor efficacy and off-target toxicity. A series of rGel-based immunotoxins were created from the human anti-Her2/neu scFv C6.5 and various affinity mutants (designated ML3-9, MH3-B1, and B1D3) with affinities ranging from 10 À8 to 10 À11 mol/L. Against Her2/neu-overexpressing tumor cells, immunotoxins with increasing affinity displayed improved internalization and enhanced autophagic cytotoxicity. Targeting indices were highest for the highest affinity B1D3/rGel construct. However, the addition of free Her2/neu extracellular domain (ECD) significantly reduced the cytotoxicity of B1D3/rGel because of immune complex formation. In contrast, ECD addition had little impact on the lower affinity constructs in vitro. In vivo studies against established BT474 M1 xenografts showed growth suppression by all immunotoxins. Surprisingly, therapy with the B1D3-rGel induced significant liver toxicity because of immune complex formation with shed Her2/neu antigen in circulation. The MH3-B1/rGel construct with intermediate affinity showed effective tumor growth inhibition without inducing hepatotoxicity or complex formation. These findings show that while high-affinity constructs can be potent antitumor agents, they may also be associated with mistargeting through the facile formation of complexes with soluble antigen leading to significant off-target toxicity.

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Affinity and Avidity in Antibody-Based Tumor Targeting

Cited by 202 publications

References 34 publications

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Single-Chain Antibody-Based Immunotoxins Targeting Her2/neu: Design Optimization and Impact of Affinity on Antitumor Efficacy and Off-Target Toxicity

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