The Effect of Antibody Fragments on CD25 Targeted Regulatory T Cell Near-Infrared Photoimmunotherapy

Abstract

Regulatory T (Treg) cells play a major role in immune suppression permitting tumors to evade immune surveillance. Depletion of intratumoral Treg cells can result in tumor regression. However, systemic depletion of Tregs may also induce autoimmune adverse events. Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cell-specific cancer therapy that locally kills specific cells in the tumor. Antibody-photoabsorber (IRDye700DX) conjugates (APC) are injected and bind to the tumor, and subsequent administration of NIR light to the tumor results in rapid cell death only in targeted cells. CD25-targeted NIR-PIT has been shown to induce spatially selective depletion of tumor-associated Treg cells. In this study, we compared the efficacy of an antibody fragment, anti-CD25-F(ab′) 2 , and a full antibody, anti-CD25-IgG, as agents for NIR-PIT. Tumor-bearing mice were divided into four groups: (1) no treatment; (2) anti-CD25-IgG-IR700 i.v. only; (3) anti-CD25-F(ab′) 2 -IR700 i.v. with NIR light exposure; and (4) anti-CD25-IgG-IR700 i.v. with NIR light exposure. Although both CD25targeted NIR-PITs resulted in significant tumor growth inhibition, the anti-CD25-F(ab′) 2 -IR700 based NIR-PIT was superior to the anti-CD25-IgG-IR700 NIR-PIT. The anti-CD25-F(ab′) 2 -IR700 demonstrated faster clearance from the body than the anti-CD25-IgG-IR700. Sustained circulation of anti-CD25-IgG-IR700 may block IL-2 binding on the activated effector T-cells decreasing immune response. In conclusion, anti-CD25-F(ab′) 2 based NIR-PIT was more effective in reducing tumor growth than anti-CD25-IgG based NIR-PIT. Absence of the Fc portion of the APC leads to faster clearance and therefore promotes a superior activated T cell response in tumors.

Highly versatile cancer photoimmunotherapy using photosensitizer-conjugated avidin and biotin-conjugated targeting antibodies

“…faster clearance from the circulation and lower tumor retention, it is also likely to be superior in terms of rapid tumor accumulation and better penetration into tumor tissues. Actually, previous reports demonstrated the smaller antibody fragments are advantageous in some PIT settings [24, 32].…”

Regulatory T cell targeting in cancer: Emerging strategies in immunotherapy

“…Interestingly, anti‐CD25‐F(ab’) 2 based NIR‐PIT elicited a greater antitumor immune response compared to anti‐CD25‐IgG based NIR‐PIT. The superior therapeutic efficacy of anti‐CD25‐F(ab’) 2 based NIR‐PIT was attributed to its shorter half‐life and faster clearance of the F(ab’) 2 fragment, which minimized the potential of circulating anti‐CD25 antibody‐photoabsorber dye complexes to block the IL‐2 receptor on effector T cells over long periods of time [57]. Encouragingly, the FDA recently granted fast‐track designation to a phase III clinical trial evaluating anti‐EGF receptor (EGFR) based NIR‐PIT technology for the treatment of head and neck squamous cell carcinoma (Clinical Trials.gov Identifier NCT03769506).…”

Nano-Enhanced Cancer Immunotherapy: Immunology Encounters Nanotechnology

“…For this reason, limiting Treg immune suppression is an obvious choice to enhance cancer immunotherapy. Because generalized blocking of Treg function increases the risk of severe autoimmune responses, selective depletion of Treg in the TME using nanotechnology can be particularly beneficial, as demonstrated by the selective depletion of Tregs using CD25-targeted near infrared photo-immunotherapy [ 88 , 89 ]. So far, TME-specific Treg-targeting of nanoparticles in combination with other immune therapies has not been tested, except for Ou et al, who demonstrated a synergistic effect when combining the selective delivery of Treg-specific tLyp1 peptide conjugated nanoparticles in the TME with ICIs [ 90 ].…”