Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance.

Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia.

Single chain Fv chimeric receptors, or T-bodies, are described with intracellular sequences comprising the costimulatory signaling domain of CD28 in series with the zeta-chain from the TCR complex Using an engineered human single chain Fv derived from P67, an mAb with specificity for human CD33, and a spacer comprising an Ab hinge region with either Fcgamma or part of the CD28 extracellular region, fusion molecules were constructed to test the ability of single chain designs to mediate both primary signaling and costimulation from one extracellular binding event Constructs with the CD28 signaling domain proximal and the zeta-chain distal to the membrane were found to express more efficiently in Jurkat than constructs with the opposite orientation and were capable of mediating up to 20 times more IL-2 production on stimulation with solid phase Ag when compared with transfectants expressing chimeric receptors with zeta-chain intracellular signaling domains only IL-2 production was specific to Ag challenge and was completely inhibited by incubation with free Ab of the same specificity as the extracellular binding site of the construct, but not by an isotype-matched control Ab The CD28 intracellular domain of these fusion proteins was shown to be capable of binding the p85 subunit of phosphatidylinositol 3'-kinase These constructs represent the first of a new generation of single gene multidomain chimeric receptors capable of mediating both primary and costimulatory signaling specifically from a single extracellular recognition event

Chimeric Receptors Providing Both Primary and Costimulatory Signaling in T Cells from a Single Gene Product

A diverse array of tumor targeting agents ranging in size from peptides to nanoparticles is currently under development for applications in cancer imaging and therapy. However, it remains largely unclear how size differences among these molecules influence their targeting properties. Here, we develop a simple, mechanistic model that can be used to understand and predict the complex interplay between molecular size, affinity, and tumor uptake. Empirical relationships between molecular radius and capillary permeability, interstitial diffusivity, available volume fraction, and plasma clearance were obtained using data in the literature. These relationships were incorporated into a compartmental model of tumor targeting using MATLAB to predict the magnitude, specificity, time dependence, and affinity dependence of tumor uptake for molecules across a broad size spectrum. In the typical size range for proteins, the model uncovers a complex trend in which intermediate-sized targeting agents (MW, approximately 25 kDa) have the lowest tumor uptake, whereas higher tumor uptake levels are achieved by smaller and larger agents. Small peptides accumulate rapidly in the tumor but require high affinity to be retained, whereas larger proteins can achieve similar retention with >100-fold weaker binding. For molecules in the size range of liposomes, the model predicts that antigen targeting will not significantly increase tumor uptake relative to untargeted molecules. All model predictions are shown to be consistent with experimental observations from published targeting studies. The results and techniques have implications for drug development, imaging, and therapeutic dosing.

/pdf/a-modeling-analysis-of-the-effects-of-molecular-size-and-qea10v3a4b.pdf

A modeling analysis of the effects of molecular size and binding affinity on tumor targeting

The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has demonstrated potential involves the selective targeting of radionuclides to cancer-associated cell surface antigens using monoclonal antibodies. Such radioimmunotherapy (RIT) permits the delivery of a high dose of therapeutic radiation to cancer cells, while minimizing the exposure of normal cells. Although this approach has been investigated for several decades, the cumulative advances in cancer biology, antibody engineering and radiochemistry in the past decade have markedly enhanced the ability of RIT to produce durable remissions of multiple cancer types.

/pdf/radioimmunotherapy-of-human-tumours-3y2zzuveuu.pdf

Radioimmunotherapy of human tumours

Radiolabeled antibodies have produced encouraging remissions in patients with chemotherapy-resistant hematological malignancies; however, the selection of therapeutic radionuclides for clinical trials remains controversial. In this study, we compared the internalization, lysosomal targeting, metabolism, and cellular retention of radiolabeled murine and humanized monoclonal antibodies targeting the CD33 antigen (monoclonal antibodies mP67 and hP67, respectively) on myeloid leukemia cell lines (HEL and HL-60) and of anti-carcinoma antibodies (monoclonal antibodies hCTM01 and hA33) targeting breast cancer and colorectal carcinoma cell lines (MCF7 and Colo 205, respectively). Each antibody was labeled with 125I (by the IodoGen method) and with 111In and 90Y using macrocyclic chelation technology. Targeted tumor cells were analyzed for retention and metabolism of radioimmunoconjugates using cellular-radioimmunoassays, Percoll gradient fractionation of cell organelles, SDS-PAGE, and TLC of cell lysates and culture supernatants. Our results suggest that antibodies are routed to lysosomes after endocytosis, where they are proteolytically degraded. [125I]monoiodotyrosine is rapidly excreted from cells after lysosomal catabolism of antibodies radioiodinated by conventional methods, whereas small molecular weight 111In and 90Y catabolites remain trapped in lysosomes. As a consequence of the differential disposition of small molecular weight catabolites, 111In and 90Y conjugates displayed superior retention of radioactivity compared with 125I conjugates when tumor cells were targeted using rapidly internalizing antibody-antigen systems (e.g., hP67 with HEL cells and hCTM01 with MCF7 cells). When tumor cells were targeted using antibody-antigen systems exhibiting slow rates of endocytosis (e.g., hP67 on HL-60 cells and hA33 on Colo 205 cells), little differences in cellular retention of radioactivity was observed, regardless of whether 125I, 111In, or 90Y was used.

https://cancerres.aacrjournals.org/content/canres/56/9/2123.full.pdf

Comparative metabolism and retention of iodine-125, yttrium-90, and indium-111 radioimmunoconjugates by cancer cells

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Comparative metabolism and retention of iodine-125, yttrium-90, and indium-111 radioimmunoconjugates by cancer cells