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Oncotarget: Targeting mesothelin with high cytotoxic activity


Here is a link to a video interview with Dr. Ira Pastan about this research on the Oncotarget YouTube Channel

Oncotarget published "Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity" which reported that Recombinant immunotoxins are genetically engineered proteins being developed to treat cancer.

They are composed of an Fv that targets a cancer antigen and a portion of a protein toxin.

Starting with an immunotoxin that has B-cell epitopes suppressed, the authors added mutations step-wise that suppress T-cell epitopes.

The final protein has greatly reduced antigenicity as assessed by binding to human anti-sera and a greatly decreased ability to activate helper T-cells evaluated in a T-cell activation assay.

LMB-T14 produces complete remissions of a mesothelin expressing cancer xenograft. The approach used in this Oncotarget study can be used to de-immunize other therapeutic foreign proteins.

The approach used in this Oncotarget study can be used to de-immunize other therapeutic foreign proteins

Dr. Ira Pastan from The National Cancer Institute, National Institutes of Health said, "Recombinant immunotoxins (RITs) are antibody-toxin fusion proteins developed for cancer therapy."

The antibodies involved in the immunogenicity response against SS1P mostly react with PE38, the toxin portion of the RIT.

The formation of high affinity IgG is primarily dependent on activation of three cellular entities:

  1. Antigen presenting cells that process the antigen and present it to T-cells,
  2. T-helper cells that secrete cytokines that are required for class switching and,
  3. affinity maturation of B-cells, which then differentiate and secrete antibodies.

B-cells produce antibodies that can bind directly to the surface of the protein, whereas helper T-cells recognize peptides that are derived from the protein and are presented by HLA class II molecules.

Elimination of a T-cell epitopes in the protein IFNβ resulted in elimination of ADA response in BALB/c mice.

Similarly, they recently demonstrated that elimination of two murine T-cell epitopes in SS1P resulted in elimination of anti-SS1P antibodies in mice.

The authors previously reported the location of the eight human T-cell epitopes in the PE38 portion of immunotoxins and used this information to construct LMB-T20, a recombinant immunotoxin that targets mesothelin and has 80% of its T-cell epitopes diminished by introducing six point mutations in domain III and deleting a large portion of domain II.

The goal of this study was to make an immunotoxin reacting with mesothelin expressing cancer cells that has high cytotoxic and anti-tumor activity, and is optimized for minimal reactivity with the adaptive immune system by suppressing both B- and T-cell epitopes.

Figure 5: Stimulation of PBMC from 10 donors with LMB-T20, LMB-T14 and SS1P. PBMC from 10 naïve donors were stimulated with either SS1P LMB-T14 or LMB-T20. After 14 days of in vitro expansion cells were re-stimulated with either 111 peptides spanning the sequence of PE38, 76 peptides spanning the sequence of LMB-T14 or LMB-T20, respectively. T-cell activation was detected using IL-2 ELISpot. Response strength is shown in the Spot Forming Cells ladder. Red stars represent mutations of T-cell epitopes, blue stars for B-cell mutations and green stars for both B and T-cell mutations.

The Pastan Research Team concluded in their Oncotarget Priority Research Paper that when incorporating multiple point mutations into a molecule, there is the risk in decreasing its activity.

There is a delicate balance between the decrease in activity the molecule will endure and the benefit of the de-immunization.

This tradeoff is demonstrated in Table 1 that shows that addition of some of the de-immunizing mutations reduced the cytotoxic activity on several cancer cell lines, but not on cells from patients with mesothelioma.

It is possible that LMB-T14 may be more efficacious in patients, due to its good stability, low nonspecific toxicity in animals so higher doses can be given and low immunogenicity will allow it to be given for more cycles.

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DOI - https://doi.org/10.18632/oncotarget.9171

Full text - https://www.oncotarget.com/article/9171/text/

Correspondence to - Ira Pastan - pastani@mail.nih.gov

Keywords - epitope, immunogenicity, rational design, mesothelioma, pancreatic cancer

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