PET Images from One Representative Animal at 1 hour Post Dose: Frontal View (A) and Sagittal View (B).

<p>PET Images from One Representative Animal at 1 hour Post Dose: Frontal View (A) and Sagittal View (B).</p

Anti-oxLDL Individual Serum Concentration-Time Profiles Measured by Assay B.

<p>Anti-oxLDL Individual Serum Concentration-Time Profiles Measured by Assay B.</p

Anti-oxLDL Individual Serum Concentration−Time Profiles Measured by Assay A.

<p>Anti-oxLDL Individual Serum Concentration−Time Profiles Measured by Assay A.</p

PK Parameters following IV Administration of a Single Dose of 10 mg/kg of Anti-oxLDL (Assay A).

<p>SD: standard deviation.</p

Binding of anti-oxLDL (conjugated and unconjugated) to MDA-ApoB100.

<p>Binding of anti-oxLDL (conjugated and unconjugated) to MDA-ApoB100.</p

Enhanced Tumor Retention of a Radiohalogen Label for Site-Specific Modification of Antibodies

A known limitation of iodine radionuclides for labeling and biological tracking of receptor targeted proteins is the tendency of iodotyrosine to rapidly diffuse from cells following endocytosis and lysosomal degradation. In contrast, radiometal–chelate complexes such as indium-111–1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (In-111-DOTA) accumulate within target cells due to the residualizing properties of the polar, charged metal-chelate-amino acid adduct. Iodine radionuclides boast a diversity of nuclear properties and chemical means for incorporation, prompting efforts to covalently link radioiodine with residualizing molecules. Herein, we describe the Ugi-assisted synthesis of [I-125]­HIP-DOTA, a 4-hydroxy-3-iodophenyl (HIP) derivative of DOTA, and demonstration of its residualizing properties in a murine xenograft model. Overall, this study displays the power of multicomponent synthesis to yield a versatile radioactive probe for antibodies across multiple therapeutic areas with potential applications in both preclinical biodistribution studies and clinical radioimmunotherapies

An Anti-B7-H4 Antibody–Drug Conjugate for the Treatment of Breast Cancer

B7-H4 has been implicated in cancers of the female reproductive system and investigated for its possible use as a biomarker for cancer, but there are no preclinical studies to demonstrate that B7-H4 is a molecular target for therapeutic intervention of cancer. We provide evidence that the prevalence and expression levels of B7-H4 are high in different subtypes of breast cancer and that only a few normal tissues express B7-H4 on the cell membrane. These profiles of low normal expression and upregulation in cancer provide an opportunity for the use of antibody–drug conjugates (ADCs), cytotoxic drugs chemically linked to antibodies, for the treatment of B7-H4 positive cancers. We have developed an ADC specific to B7-H4 that uses a linker drug consisting of a potent antimitotic, monomethyl auristatin E (MMAE), linked to engineered cysteines (THIOMAB) via a protease labile linker. We will refer to ADCs that use the THIOMAB format as TDCs to help distinguish the format from standard MC-vc-MMAE ADCs that are conjugated to the interchain disulfide bonds. Anti-B7-H4 (h1D11)-MC-vc-PAB-MMAE (h1D11 TDC) produced durable tumor regression in cell line and patient-derived xenograft models of triple-negative breast cancer. It also binds rat B7-H4 with similar affinity to human and allowed us to test for target dependent toxicity in rats. We found that our anti-B7-H4 TDC has toxicity findings similar to untargeted TDC. Our results validate B7-H4 as an ADC target for breast cancer and support the possible use of this TDC in the treatment of B7-H4⁺ breast cancer