Therapeutic potential of an anti-HER2 single chain antibody–DM1 conjugates for the treatment of HER2-positive cancer

Abstract

Antibody–drug conjugates (ADCs) take the advantage of monoclonal antibodies to selectively deliver highly potent cytotoxic drugs to tumor cells, which have become a powerful measure for cancer treatment in recent years. To develop a more effective therapy for human epidermal growth factor receptor 2 (HER2)-positive cancer, we explored a novel ADCs composed of anti-HER2 scFv–HSA fusion antibodies conjugates with a potent cytotoxic drug DM1. The resulting ADCs, T-SA1–DM1 and T-SA2–DM1 (drug-to-antibody ratio in the range of 3.2–3.5) displayed efficient inhibition in the growth of HER2-positive tumor cell lines and the half-maximal inhibitory concentration on SKBR-3 and SKOV3 cells were both at the nanomolar levels in vitro. In HER2-positive human ovarian cancer xenograft models, T-SA1–DM1 and T-SA2–DM1 also showed remarkable antitumor activity. Importantly, three out of six mice exhibited complete remission without regrowth in the high-dose group of T-SA1–DM1. On the basis of the analysis of luminescence imaging, anti-HER2 scFv–HSA fusion antibodies, especially T-SA1, showed strong and rapid tumor tissue penetrability and distribution compared with trastuzumab. Collectively, the novel type of ADCs is effective and selective targeting to HER2-positive cancer, and may be a promising antitumor drug candidate for further studies.

Antitumor effects of a recombinant baculovirus displaying anti-HER2 scFv expressing Apoptin in HER2 positive SK-BR-3 breast cancer cells

“…Other works have used anti-HER2 scFv antibody for targeting breast cancer cells using the Pichia pastoris as the host for the expression of antibody fragments [38] and developing anti-HER2 scFv-HSA fusion antibodies conjugates with drug DM1 [39]. In a recent study, Alric and colleagues showed the specific binding and high affinity properties of SPIONs-Cy-PEG-scFv nanoparticles against HER2 positive breast cancer cells, leading to Alric and colleagues and suggestingsuggesting the use of this nanoparticle as an imaging agents for the diagnosis of breast tumors with HER2 overexpression [40].…”

Bioprocess development of antibody-drug conjugate production for cancer treatment

“…The integrity of ADC structure was analyzed using SDS-PAGE. The average drug-antibody ratio (DAR) was calculated using the following equation [ 21 , 22 ]: Where R = A 248 /A 280 = Absorbance ratio. ε mAb 248/252 = 9.41×10 4 M -1 cm -1 , ε mAb 280 = 2.34×10 5 M -1 cm -1 , ε MMAE 248 = 1.5×10 3 M -1 cm -1 , ε MMAE 280 = 1.59×10 4 M -1 cm -1 , ε DM1 252 = 2.64×10 5 M -1 cm -1 , ε DM1 280 = 5.23×10 3 M -1 cm -1 .…”

Roles of Albumin‐Binding Proteins in Cancer Progression and Biomimetic Targeted Drug Delivery

“…[59] The anti-HER2 scFv-HSA fusion Abs showed stronga nd rapid tumor tissue penetrability and distribution compared with that of trastuzumab. [59]…”

“…Other important applications include Ab fragments (e.g.,F v and Fab) and albuminf usion proteins to extend the half-life in vivo. [59] For example, compared with af ull-length Ab, scFv is smaller in size, but with similar binding activity,b etter tissue penetrability,a nd lower immunogenicity;h owever,t he drawback is its short half-life in circulation. [59] The anti-HER2 scFv-HSA fusion Abs showed stronga nd rapid tumor tissue penetrability and distribution compared with that of trastuzumab.…”