Limits...
Overcoming resistance to HER2-targeted therapy with a novel HER2/CD3 bispecific antibody

View Article: PubMed Central - PubMed

ABSTRACT

T-cell-based therapies have emerged as one of the most clinically effective ways to target solid and non-solid tumors. HER2 is responsible for the oncogenesis and treatment resistance of several human solid tumors. As a member of the HER family of tyrosine kinase receptors, its over-activity confers unfavorable clinical outcome. Targeted therapies directed at this receptor have achieved responses, although development of resistance is common. We explored a novel HER2/CD3 bispecific antibody (HER2-BsAb) platform that while preserving the anti-proliferative effects of trastuzumab, it recruits and activates non-specific circulating T-cells, promoting T cell tumor infiltration and ablating HER2(+) tumors, even when these are resistant to standard HER2-targeted therapies. Its in vitro tumor cytotoxicity, when expressed as EC50, correlated with the surface HER2 expression in a large panel of human tumor cell lines, irrespective of lineage or tumor type. HER2-BsAb-mediated cytotoxicity was relatively insensitive to PD-1/PD-L1 immune checkpoint inhibition. In four separate humanized mouse models of human breast cancer and ovarian cancer cell line xenografts, as well as human breast cancer and gastric cancer patient-derived xenografts (PDXs), HER2-BsAb was highly effective in promoting T cell infiltration and suppressing tumor growth when used in the presence of human peripheral blood mononuclear cells (PBMC) or activated T cells (ATC). The in vivo and in vitro antitumor properties of this BsAb support its further clinical development as a cancer immunotherapeutic.

No MeSH data available.


Related in: MedlinePlus

HER2-BsAb is effective against HER2(+) ovarian cancer cell line xenografts. Treatment schedules were marked on the figures, and doses of BsAbs and effector cells were detailed in the Results. Data shown as mean + SEM (n = 4). (A) ip tumor plus ip/iv effector cells model: Bioluminescence changes of SKOV3-luc ovarian cancers during treatment. (B) Representative bioluminescence images at the beginning (Day 13) and ending (Day 34) of the treatment were shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC5384386&req=5

f0005: HER2-BsAb is effective against HER2(+) ovarian cancer cell line xenografts. Treatment schedules were marked on the figures, and doses of BsAbs and effector cells were detailed in the Results. Data shown as mean + SEM (n = 4). (A) ip tumor plus ip/iv effector cells model: Bioluminescence changes of SKOV3-luc ovarian cancers during treatment. (B) Representative bioluminescence images at the beginning (Day 13) and ending (Day 34) of the treatment were shown.

Mentions: To determine the in vivo efficacy of HER2-BsAb, the breast carcinoma cell lines HCC1954 (HER2high), MCF-7 (HER2low) and ovarian carcinoma cell line SKOV3, as well as HER2(+) patient derived breast cancer and gastric cancer xenografts (PDXs) were used in DKO mice xenograft models. Four tumor models differing in tumor locations and effector routes were used, with the first three described before20 to simulate different clinical situations: (1) iv tumor cells/iv effector PBMC; (2) sc tumor cells/sc PBMC; (3) sc tumor cells/iv PBMC; and (4) ip tumor cells plus ip or iv effector T cells to simulate ovarian cancer metastasizing to the peritoneal cavity. Figs. 4 and 5 summarize the results of these experiments using cell lines, and Fig. 6 using PDXs (M37 breast cancer and EK gastric cancer).Figure 4.


Overcoming resistance to HER2-targeted therapy with a novel HER2/CD3 bispecific antibody
HER2-BsAb is effective against HER2(+) ovarian cancer cell line xenografts. Treatment schedules were marked on the figures, and doses of BsAbs and effector cells were detailed in the Results. Data shown as mean + SEM (n = 4). (A) ip tumor plus ip/iv effector cells model: Bioluminescence changes of SKOV3-luc ovarian cancers during treatment. (B) Representative bioluminescence images at the beginning (Day 13) and ending (Day 34) of the treatment were shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5384386&req=5

f0005: HER2-BsAb is effective against HER2(+) ovarian cancer cell line xenografts. Treatment schedules were marked on the figures, and doses of BsAbs and effector cells were detailed in the Results. Data shown as mean + SEM (n = 4). (A) ip tumor plus ip/iv effector cells model: Bioluminescence changes of SKOV3-luc ovarian cancers during treatment. (B) Representative bioluminescence images at the beginning (Day 13) and ending (Day 34) of the treatment were shown.
Mentions: To determine the in vivo efficacy of HER2-BsAb, the breast carcinoma cell lines HCC1954 (HER2high), MCF-7 (HER2low) and ovarian carcinoma cell line SKOV3, as well as HER2(+) patient derived breast cancer and gastric cancer xenografts (PDXs) were used in DKO mice xenograft models. Four tumor models differing in tumor locations and effector routes were used, with the first three described before20 to simulate different clinical situations: (1) iv tumor cells/iv effector PBMC; (2) sc tumor cells/sc PBMC; (3) sc tumor cells/iv PBMC; and (4) ip tumor cells plus ip or iv effector T cells to simulate ovarian cancer metastasizing to the peritoneal cavity. Figs. 4 and 5 summarize the results of these experiments using cell lines, and Fig. 6 using PDXs (M37 breast cancer and EK gastric cancer).Figure 4.

View Article: PubMed Central - PubMed

ABSTRACT

T-cell-based therapies have emerged as one of the most clinically effective ways to target solid and non-solid tumors. HER2 is responsible for the oncogenesis and treatment resistance of several human solid tumors. As a member of the HER family of tyrosine kinase receptors, its over-activity confers unfavorable clinical outcome. Targeted therapies directed at this receptor have achieved responses, although development of resistance is common. We explored a novel HER2/CD3 bispecific antibody (HER2-BsAb) platform that while preserving the anti-proliferative effects of trastuzumab, it recruits and activates non-specific circulating T-cells, promoting T cell tumor infiltration and ablating HER2(+) tumors, even when these are resistant to standard HER2-targeted therapies. Its in vitro tumor cytotoxicity, when expressed as EC50, correlated with the surface HER2 expression in a large panel of human tumor cell lines, irrespective of lineage or tumor type. HER2-BsAb-mediated cytotoxicity was relatively insensitive to PD-1/PD-L1 immune checkpoint inhibition. In four separate humanized mouse models of human breast cancer and ovarian cancer cell line xenografts, as well as human breast cancer and gastric cancer patient-derived xenografts (PDXs), HER2-BsAb was highly effective in promoting T cell infiltration and suppressing tumor growth when used in the presence of human peripheral blood mononuclear cells (PBMC) or activated T cells (ATC). The in vivo and in vitro antitumor properties of this BsAb support its further clinical development as a cancer immunotherapeutic.

No MeSH data available.


Related in: MedlinePlus