Antibodies conjugated with diagnostic/therapeutic radionuclides are attractive options for inoperable cancers lacking accurate imaging methods and effective therapeutics, such as pancreatic cancer. Hence, we have produced an antibody radionuclide conjugate termed TE-1132 comprising a α-CA19-9 scFv-Fc that is site-specifically conjugated at each C-terminus to 3 DOTA chelators via a cysteine-containing peptide linker. The smaller scFv-Fc size facilitates diffusivity within solid tumors, whereas the chelator-to-antibody ratio of six enabled 177 Luradiolabeled TE-1132 to exhibit high radioactivity up to 520 MBq/nmol. In mice bearing BxPC3 tumors, immuno-SPECT/CT imaging of [ 111 In]In-TE-1132 and the biodistribution of [ 177 Lu]Lu-TE-1132 showed selective tumor accumulation. Single and multiple doses of [ 177 Lu]Lu-TE-1132 effectively inhibited the BxPC3 tumor growth and prolonged the survival of mice with no irreversible body weight loss or hematopoietic damage. The adequate pharmacokinetic parameters, prominent tumor accumulation, and efficacy with good safety in mice encourage the further investigation of theranostic TE-1132 for treating pancreatic cancer.

Therapeutics reducing bone turnover, such as denosumab (Dmab), an anti-RANKL antibody, can provide treatments for patients with bone destruction. However, some patients with osteoporosis or localized primary bone tumors and many patients with various types of bone-metastatic cancer display unsatisfactory responses to Dmab. For achieving greater efficiency of RANKL neutralization in the bone microenvironment by enhancing the distribution of Dmab to the bone, we reengineered Dmab by fusing with single-chain variable fragments of an antibody specific for osteonectin (On), which is abundantly expressed in osseous tissues. The bispecific antibody, Dmab-FvOn, showed a similar activity as Dmab in inhibiting RANKL as examined in an osteoclast differentiation assay. When administered to mice, Dmab-FvOn was found to localize in increased proportions at the endosteum of the bone where osteonectin is abundant. Our study suggests that by linking anti-RANKL with an osteonectin-targeting moiety, a greater proportion of the therapeutic effector can be distributed in the bone. Future studies are needed to investigate whether the bispecific antibody can achieve higher therapeutic efficacy and lower toxicity.

Caspase‐3 down‐regulation (CASP3/DR) in tumors frequently confers resistance to cancer therapy and is significantly correlated with a poor prognosis in cancer patients. Because CASP3/DR cancer cells rely heavily on the activity of caspase‐7, an executioner caspase that is similar to caspase‐3, to initiate apoptosis, the inhibition of activated caspase‐7 (p19/p12‐casp7) by XIAP is considered a possible mechanism for the prevention of apoptosis in those cancer cells. Here, we identify the pocket surrounding the Cys246 residue of p19/p12‐casp7 as a target for the development of a protein‐protein interaction (PPI) inhibitor of the XIAP:p19/p12‐casp7 complex. We demonstrate that interrupting this PPI directly triggers caspase‐7‐dependent apoptotic signaling that bypasses the activation of the apical caspases and selectively kills CASP3/DR malignancies in vitro and in vivo without adverse side effects in non‐tumor cells. Importantly, CASP3/DR combined with p19/p12‐casp7 accumulation correlates with the aggressive evolution of clinical malignancies and a poor prognosis in cancer patients. Moreover, the targeting of this PPI effectively kills cancer cells with multidrug resistance due to miR‐let‐7a1‐mediated CASP3/DR and re‐sensitizes cancer cells to chemotherapy‐induced apoptosis. These findings not only provide an opportunity to treat CASP3/DR malignancies by targeting the XIAP:p19/p12‐casp7 complex but also elucidate the molecular mechanism underlying CASP3/DR in cancers.