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Oncotarget Molecular imaging reveals biodistribution of P-cadherin LP-DART bispecific


Oncotarget Volume 11 Issue 15 reported that P-cadherin-LP-DART is a bispecific antibody targeting P-cadherin expressed on the tumor cells and CD3 on the T-cells.

P-cadherin-LP-DART accumulation in the tumor was 20-25 fold higher compared to Control-LP-DART demonstrating the targeting specificity.

Imaging after engraftment of CV815 labeled T-cells showed P-cadherin-LP-DART mediated T-cell trafficking in tumors.

Dr. Anand Giddabasappa from Global Science & Technology (GST) – Comparative Medicine, Pfizer Global Research Development and Medical, San Diego, CA 92121, USA said, "Antibody-based therapeutic platforms have revolutionized the biopharmaceutical landscape in last two decades."

"Antibody-based therapeutic platforms have revolutionized the biopharmaceutical landscape in last two decades."

- Dr. Anand Giddabasappa, Global Science & Technology (GST) – Comparative Medicine, Pfizer Global Research Development and Medical

Immune effector cells that can be engaged by bispecific antibodies include T cells, Natural Killer cells, and Macrophages.

Mechanistically, bispecific antibodies targeting effector T cells co-engage the CD3 epsilon subunit on the T cells and specific antigen on tumor cells to form a bispecific mediated synapse.

However, the development of these next-generation biologics is increasingly complex and often requires intricate protein engineering approaches to create novel scaffolds and technology platforms.

The bispecific antibody formats can be broadly categorized as:

  • A) conventional Ig G like bispecific antibodies that retain Fc-mediated effector antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity functionalities or
  • B) novel non-Ig G like bispecific antibodies that generally have dual binding functionality with minimal or no effector functions.

The dual-affinity re-targeting platform is a bispecific molecular format that can co-engage the TCR/CD3 complex on effector T cells and a targeting antigen on tumor cells.

P-cadherin LP-DART is a bispecific molecule that uses the DART platform to bind CD3 epsilon on the T cells and P-cadherin on the tumor cells.

The Umetani/Wu Research Team concluded in their Oncotarget Research Paper that the pharmacology of the bispecific antibody is elicited by forming a bridge between the target cell and the effector cell.

Advances in immunotherapy, along with the interest in tracking immune cells in vivo in patients and in pre-clinical models, has resulted in the development of multiple molecular imaging methodologies.

Figure 1: Schematic of the bispecific reagents used in this study. (A) Representation of the individual chains of anti-P-cadherin human IgG1 Fc-containing DART, also referred to as P-cadherin LP-DART. Cysteine residues introduced for interchain disulfide formation are indicated by C. EFN, effector function null mutations in CH2. Knob, hole: complementary mutations introduced to force Fc heterodimerization [10–12]. (B) Schematic representation of the folded P-cadherin LP-DART protein after heterodimerization. (C) Representation of the anti-P-cadherin single chain diabody (scDb) DART linear expression construct. Cysteine residue introduced for site specific conjugation at the C-terminus is indicated by C. (D) Schematic representation of the folded anti-P-cadherin DART (scDb) protein.

Although CV815 based T cell tracking has several advantages, it may underestimate the number of T cells since the fluorescence is diluted by one-half at each subsequent division of the proliferating T cell.

In summary, using FMT imaging we have shown the targeting of P-cadherin LP-DART and the trafficking of T cells to the tumor microenvironment in pre-clinical models.

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DOI - https://doi.org/10.18632/oncotarget.27544

Full text - https://www.oncotarget.com/article/27544/text/

Correspondence to - Anand Giddabasappa - anand.giddabasappa@pfizer.com

Keywords - bispecific antibody, tumor targeting, biodistribution, T cells, molecular imaging

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