Robert W. Kozak

Metal-chelate-dendrimer-antibody constructs for use in radioimmunotherapy and imaging

Polyamidoamine dendrimers were modified chemically by reaction with DOTA and DTPA type bifunctional metal chelators and were coupled to monoclonal antibody 2E4 without loss of protein immunoreactivity. Both the DTPA- and DOTA-dendrimer-antibody constructs were easily labeled with 90Y, 111In, 212Bi or cold Gd(III) suggesting use of this dendrimer-macrocycle for mAb guided radiotherapy or imaging.

Type I and II insulin-like growth factor receptors on human phytohemagglutinin-activated T lymphocytes☆

Human T cells activated with mitogens, antigens, or antibodies to the T-cell receptor complex acquire a cascade of new receptors, including the receptors for interleukin-2, transferrin, and insulin. We investigated whether receptors for insulin-like growth factors (IGF) also were expressed on activated T cells. Based on competitive binding studies, immunoprecipitation of labeled cell surface receptors and blocking of radiolabeled peptide binding by a specific monoclonal antibody (alpha IR-3) to the type I IGF receptor, as well as affinity crosslinking of radiolabeled peptides to their receptors, we concluded that both type I and type II IGF receptors are expressed on activated T cells. A specific binding site for IGF-II also was observed on the type I IGF receptor which was not inhibited by alpha IR-3. Receptors for IGF were more numerous on activated T cells than on resting T cells, and their peak expression appeared by the peak of DNA synthesis. Thus, human activated T cells were shown to express both type I and II IGF receptors which could potentially play a role in the regulation of T-cell proliferation, differentiation, and function.

IL-2 receptors in adult T-cell leukemia: a target for immunotherapy.

The induction of a T-cell immune response to a foreign antigen requires the activation of T-lymphocytes that is initiated by the interaction of the T-cell antigen receptor with antigen presented in the context of products of the major histocompatibility locus and the macrophage-derived interleukin-1. Following this interaction, T cells express the gene encoding the lymphokine interleukin-2 (IL-2) [1,2]. To exert its biological effect, IL-2 must interact with specific high-affinity membrane receptors. Resting T cells do not express IL-2 receptors, but receptors are rapidly expressed on T cells after activation with an antigen or mitogen [3–5]. Thus, the growth factor IL-2 and its receptor are absent in resting T cells, but after activation the genes for both proteins become expressed.

Role and Molecular Biology of the Interleukin–2-Interleukin-2 Receptor System in Health and Disease

Interleukin-2 (IL-2) is a lymphokine synthesized by T cells following activation. Resting T cells do not express IL-2 receptors, but receptors are rapidly expressed on T cells following interaction of the antigen-specific T cell receptor complex with appropriately processed and presented antigens. AntiTac, a monoclonal antibody that recognizes the IL-2 receptor, has been used to purify the receptor. The receptor is a 55-kDa glycoprotein comprised of 251 amino acids as well as a single 19-amino acid transmembrane domain and a short intra-cytoplasmic domain composed of 13 amino acids at the carboxy-terminus. Normal resting T cells and most leukemic T cell populations examined did not express IL-2 receptors; however, the leukemic cells of all patients with HTLV-I-associated adult T cell leukemia (ATL) expressed the Tac antigen. In HTLV-I-infected cells, the 42-kDa tat protein encoded in part by the tat region of HTLV-I may act as a transacting activator that induces transcription of the IL-2 receptor gene, thus providing an explanation for the constant association of HTLV-I infection of lymphoid cells and IL-2 receptor expression. The constant display of large numbers of IL-2 receptors which may be aberrant in the ATL cells may play a role in the uncontrolled growth of these leukemic T cells. Patients with the Tac-positive ATL are being treated with both unmodified and toxin-conjugated forms of anti-Tac monoclonal antibody directed toward this growth factor receptor.