Redirected optimized cell killing (ROCK®): A highly versatile multispecific fit-for-purpose antibody platform for engaging innate immunity.

Redirection of immune cells to efficiently eliminate tumor cells holds great promise. Natural killer cells (NK), macrophages, or T cells are specifically engaged with target cells expressing markers after infection or neoplastic transformation, resulting in their activation and subsequent killing of those targets. Multiple strategies to redirect immunity have been developed in the past two decades, but they have technical hurdles or cause undesirable side-effects, as exemplified by the T cell-based chimeric antigen receptor approaches (CAR-T therapies) or bispecific T cell engager platforms.

Conditional inactivation of MLH1 in thymic and naive T-cells in mice leads to a limited incidence of lymphoblastic T-cell lymphomas.

Defects in the mismatch repair system (MMR) underlie hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome and also a significant number of sporadic colorectal cancers. Mice carrying a null allele for the MMR gene Mlh1 are preferentially prone to the development of lymphomas of B- and T-cell origin and to a lesser extent gastrointestinal tumors. Consistent with these findings in mice, MMR defects have also been observed in sporadic and hereditary hematological malignancies.

Phosphorylation regulates transcriptional activity of PAX3/FKHR and reveals novel therapeutic possibilities.

Inhibition of constitutive active signaling pathways, which are a characteristic phenomenon for many tumors, can be an effective therapeutic strategy. In contrast, oncogenic transcription factors, often activated by mutational events, are in general less amenable to small-molecule inhibition despite their obvious importance as therapeutic targets. One example of this is alveolar rhabdomyosarcoma (aRMS), in which specific translocations lead to the formation of the chimeric transcription factor PAX3/FKHR.

B cell-specific deficiency for Smad2 in vivo leads to defects in TGF-beta-directed IgA switching and changes in B cell fate.

Smad2 is a member of the intracellular mediators that transduce signals from TGF-beta receptors and activin receptors. Targeted inactivation of Smad2 in mice leads to early lethality before gastrulation. It was shown previously that TGF-betaRII deficiency in vivo leads to defects in B cell homeostasis, Ag responsiveness, and IgA class switch recombination of B cells.

Transposable elements as a source of genetic innovation: expression and evolution of a family of retrotransposon-derived neogenes in mammals.

A family of functional neogenes called Mart, related to the gag gene of Sushi-like long terminal repeat retrotransposons from fish and amphibians, is present in the genome of human (11 genes) and other primates, as well as in mouse (11 genes), rat, dog (12 genes), cat, and cow. Mart genes have lost their capacity of retrotransposition through non-functionalizing rearrangements having principally affected long terminal repeats and pol open reading frame. Most Mart genes are located on the X chromosome in different mammals.