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Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies I

ABSTRACT: Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies I

PROVIDER: PRJNA597032 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10748004.fastq.gz	Fastqsanger.gz
	SRR10748006.fastq.gz	Fastqsanger.gz
	SRR10748007.fastq.gz	Fastqsanger.gz
	SRR10748008.fastq.gz	Fastqsanger.gz
	SRR10748009.fastq.gz	Fastqsanger.gz

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Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies II

Project description:Alternate strategies are needed for B-cell malignancy patients relapsing after CD19-targeted immunotherapy. Here, integrated cell surface proteomics and epigenetic analysis initially revealed CD72 as an optimal target for poor-prognosis MLL-rearranged B-ALL, which we further found to be expressed widely across B-cell malignancies. Using a recently-described, fully-in vitro system we selected CD72-specific nanobodies, incorporated them into CARs, and demonstrated robust activity against B-cell malignancy models, including CD19 loss. “Antigen escape profiling” modeled membrane proteome changes in the context of CD72 loss while pharmacologic SHIP1 inhibition increased CD72 surface density. We establish CD72-nanobody CAR T’s as a promising therapy for refractory B-cell malignancies.

2021-12-17 | GSE143179 | GEO

Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies I

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Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies

Project description:Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies

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Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies

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Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies II

Project description:Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies II

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Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-12-17 | GSE143181 | GEO

Framework humanization increases the affinity and potency of anti-CD72 nanobody-based CAR-T cells for B-cell malignancies

Project description:Anti-CD19 CAR T cells can induce remissions in some patients with B-cell malignancies. However, new immunotherapeutic targets are urgently needed for the many who relapse. We recently described CD72 as a promising target in B-cell leukemia and lymphoma, developing fully synthetic nanobody-based CAR-T cells (nanoCARs) against this antigen. Toward clinical translation, here we humanize our previous nanobody framework regions, derived from llama, and surprisingly discover a clone ("H24") with enhanced potency against B-cell tumors both in vitro and in vivo. In vitro, H24 nanoCARs showed improved cytokine secretion and favorable immunophenotypic properties. RNA sequencing before and after tumor exposure reveals humanized H24 CD72 nanoCARs have unique transcriptional programs compared to CD19 CAR T cells. We further find that H24 nanoCARs lead to sustained CD72 downregulation on tumors treated in vivo. Underpinning this improved potency, H24 had higher binding affinity to CD72 compared to a fully llama framework. Further affinity maturation moderately increased cytotoxicity versus antigen-low tumors. This work supports clinical translation of H24 CD72 nanoCARs, reveals potential mechanisms of resistance to this cellular therapy, and unexpectedly demonstrates that nanoCAR potency can be improved by framework alterations alone, without any change to the complementarity determining regions (CDRs) of the nanobody sequence.

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Project description:A nanobody is an antibody fragment consisting of a single monomeric variable antigen-binding domain. Mammalian cells are ideal platforms for identifying nanobodies targeting hard-to-display transmembrane proteins and nanobodies that function as modulators of cellular phenotypes. However, the introduction of a high-diversity nanobody library into mammalian cells is challenging. We have developed two novel methods for constructing a nanobody library in mammalian cells. Complementarity-determining region (CDR) random sequences were first incorporated into upstream and downstream dsDNAs by PCR. In the first method, named dsDNA-HR, upstream and downstream dsDNAs containing an identical overlapping sequence were co-transfected into cultured mammalian cells for intracellular homologous recombination that resulted in the formation of an intact nanobody library expression cassette. In the second method, named in vitro ligation, we generated full-length nanobody expression dsDNAs via ligation of restriction digested upstream and downstream dsDNAs. The obtained full-length dsDNAs were transfected into mammalian cells for nanobody library expression. Using both methods, we generated over a million unique nanobody sequences, as revealed by high-throughput sequencing. Single-cell sequencing was employed to resolve the diversity of the dsDNA-HR nanobody library. We also identified a small molecule, Nocodazole, which could enhance the efficacy of dsDNA-HR.

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