D domain (DD) containing polypeptides (DDpp) that specifically bind targets of interest (e.g., BCMA, CD123, CS1, HER2, AFP, and AFP p26) are provided, as are nucleic acids encoding the DDpp, vectors containing the nucleic acids and host cells containing the nucleic acids and vectors. DDpp such as DDpp fusion proteins, are also provided as are methods of making and using the DDpp. Such uses include, but are not limited to diagnostic and therapeutic applications.

Provided for herein in several embodiments are anti-BCMA binding moieties. These anti-BCMA binding moieties may be used in BCMA-directed chimeric antigen receptors (CARs). Also disclosed herein are immune cell-based compositions comprising the anti-BCMA binding moieties and BCMA-directed CARs. In several embodiments, the immune-cell based compositions also target an additional tumor marker and/or an additional epitope of BCMA. In several embodiments, the BCMA-directed CAR is expressed in a Natural Killer cell. In several embodiments, combinations of BCMA-CAR-expressing NK cells are administered in conjunction with, for example CAR-expressing NK cells and/or CAR-expressing T cells that are directed to an additional cancer marker and/or an additional epitope of BCMA. Also provided for herein are methods and uses of the chimeric antigen receptors in immunotherapy.

Disclosed herein are polynucleotides and vectors encoding improved immunotherapeutics, polypeptides encoded by the polynucleotides and/or vectors, cells expressing the polypeptides, and pharmaceutical compositions comprising the polynucleotides, vectors, polypeptides, and/or cells.

The disclosure provides a chimeric antigen receptor (CAR) comprising a modified hinge, transmembrane and/or intracellular domain disclosed herein. Some aspects of the disclosure relate to a polynucleotide encoding a chimeric antigen receptor (CAR) comprising the costimulatory domain disclosed herein. Other aspects of the disclosure relate to cells comprising the CAR and use in a T cell therapy.

The present disclosure provides bispecific chimeric antigen receptors targeting CD20 and BCMA. The CAR may comprise an scFv targeting CD20 and an scFv targeting BCMA, a hinge region, a transmembrane domain, a co-stimulatory region, and a cytoplasmic signaling domain. The chimeric antigen receptors can be used to treat autoimmune disorders or cancer.

The present disclosure provides humanized antibodies and antigen binding domains thereof that bind CD8 and other antibody formats comprising these antigen binding domains, their use as a targeting moiety on lipid nanoparticles (tLNP) to deliver a therapeutic payload (such as a nucleic acid molecule) or other types of payloads. The present disclosure further relates to pharmaceutical compositions comprising the humanized anti-CD8 antibodies and CD8-targeted tLNP encapsulating a payload.

The present disclosure is directed to leucine zipper-based sorting systems adapted to facilitate the expression and coordination of polypeptide sequences capable of improving the function of CAR T cells. The systems enable the generation of T cells engineered to express multiple combinations of CARs (multi-CAR), safety-switches, switch receptors, and/or cytokines.

The present invention relates generally to a population of stem cells (e.g., iPSCs or HSCs) that comprise nucleic acids encoding a T cell receptor and a chimeric antigen receptor directed to multiple distinct antigenic determinants, for example two distinct tumour antigenic determinants. The present invention is also directed to a population of T cells that co-express a T cell receptor and a chimeric antigen receptor directed to multiple distinct antigenic determinants, such as two distinct tumour antigenic determinants. The cells of the present invention can be derived from chosen donors whose HLA type is compatible with significant sectors of the populations, and are useful in a wide variety of applications, in particular in the context of the therapeutic treatment of neoplastic conditions.

The present disclosure relates to systems and methods for immune therapy. For example, a method can be used to enhance the proliferation of chimeric antigen receptor (CAR) T cells in a subject, The method comprises administering to the subject an effective amount of a pharmaceutical composition comprising one or more lymphocyte activation agents and one or more recombinant viral particles comprising a polynucleotide encoding a CAR, wherein the proliferation of CAR T cells in the subject is greater than in a subject administered with the one or more recombinant viral particles but without the lymphocyte activation agent.

Provided are methods and compositions for obtaining functionally enhanced derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. The derivative cells provided herein have stable and functional genome editing that delivers improved or enhanced therapeutic effects. Also provided are therapeutic compositions and uses thereof comprising the functionally enhanced derivative effector cells alone, or with antibodies or checkpoint inhibitors in combination therapies.