Tumor-targeting anti-EGFR x anti-PD1 bispecific antibody inhibits EGFR-overexpressing tumor growth by combining EGFR blockade and immune activation with direct tumor cell killing

Abstract

Highlights The anti-PD1 x anti-EGFR bispecific antibody (BsAb) exhibited all in-vitro bioactivities comparable to that of the parental mAbs and showed anti-tumor efficacies of each of the two arms on par with the mAbs in-vivo. The anti-PD1 x anti-EGFR bispecific antibody (BsAb) retained full ADCC towards cancer cells but not to T cells. Thus the BsAb is capable of killing tumor cells via ADCC while sparing T cells for T cell-induced anti-tumor immunity. The anti-PD1 x anti-EGFR bispecific antibody (BsAb) exhibited significantly stronger tumor cell killing effects in the presence of PBMC relative to that of combination of cetuximab with an anti-PD1 mAb, 609A.

Bispecific antibody simultaneously targeting PD1 and HER2 inhibits tumor growth via direct tumor cell killing in combination with PD1/PDL1 blockade and HER2 inhibition

“…4b ). This result is in line with the previous finding where a BsAb with anti-PD1 scFvs fused to the N-terminus of cetuximab showed no ADCC toward T cells [ 39 ]. This suggests that proper spacing between the cell surface receptors and the Fc region of an IgG molecule or a favorable protein configuration as a whole, such as an intact IgG format, might be a critical determinant for initiating ADCC.…”

“…Given that the BsAb can crosslink PD1 on T cells and HER2 on tumor cells, we hypothesized that the BsAb may enhance tumor cell killing by bringing T cells into the proximity of tumor cells and potentially inducing PD1 synapse formation as seen in our previous study [ 39 ]. We stably transfected NCI-N87 cells, a HER2-overexpressing gastric cancer cell line that does not express PDL1 when cultured in vitro (data not shown), with a PDL1 construct to obtain a PDL1/HER2 double-overexpressing cancer cell line (N87-PDL1) that could potentially respond to trastuzumab and anti-PD1 mAbs.…”

“…A BsAb can bridge its two target antigens and bring them into close proximity [ 36 ]. A BsAb can retarget the effector cells, e.g., T cells, against tumor cells by simultaneously binding to cell surface antigens expressed from both cells and thus significantly activate the antitumor activities of effector cells [ 37 – 39 ]. A BsAb can also ligate two different receptors on the same cell and change intracellular downstream signaling [ 40 ].…”

Emerging new therapeutic antibody derivatives for cancer treatment

“…149 Moreover, checkpoint blockades have been incorporated into BsAbs to achieve tumorlocalized and TAA-dependent checkpoint blockage. 150,151 For example, an anti-PD-1 × HER2 (human epidermal growth factor receptor 2) BsAb (IBI315, Innovent, Inc., China) was designed to bridge PD-1-expressing T cells to HER2-expressing tumor cells, block the PD-1/PD-L1 signaling pathway in a HER2-dependent manner, and inhibit activation of the HER2 signaling pathway. 152 As a result, IBI315 combines targeted therapy with immunotherapy, thereby potentially enhancing antitumor activity via multiple mechanisms of action.…”

“…Similarly, an anti-PD-1 × EGFR IgG scaffold-based BsAb has exhibited potent antitumor efficacy and enhanced T cell-based antitumor immunity through PD-L1 blockade in both in vitro and in vivo models. 151 Simultaneous blockade of two immune checkpoints with synergic mechanisms of action has been used to maximize checkpoint blockade in the TME. 153 , 154 A clinical trial showed that five-year outcomes of applying nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) to treat patients with advanced melanoma led to sustained long-term OS compared with treatment with ipilimumab alone, 155 providing a rationale for concurrently targeting two immune checkpoints.…”