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CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas.

Oberst MD, Fuhrmann S, Mulgrew K, Amann M, Cheng L, Lutterbuese P, Richman L, Coats S, Baeuerle PA, Hammond SA - MAbs (2014)

Bottom Line: Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome.The potency of in vitro lysis was dependent on CEA antigen density but independent of the mutational status in cancer cell lines.Importantly, individual or combinations of mutated KRAS and BRAF oncogenes, activating PI3KCA mutations, loss of PTEN expression, and loss-of-function mutations in TP53 did not reduce the activity in vitro.

View Article: PubMed Central - PubMed

Affiliation: a MedImmune LLC ; Gaithersburg , MD USA.

ABSTRACT
Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome. Novel therapeutics with mechanisms of action that are independent of mutational status would therefore fulfill a current unmet clinical need. Here the CEA and CD3 bispecific single-chain antibody MEDI-565 (also known as MT111 and AMG 211) was evaluated for its ability to activate T cells both in vitro and in vivo and to kill human tumor cell lines harboring various somatic mutations commonly found in colorectal cancers. MEDI-565 specifically bound to normal and malignant tissues in a CEA-specific manner, and only killed CEA positive cells. The BiTE® antibody construct mediated T cell-directed killing of CEA positive tumor cells within 6 hours, at low effector-to-target ratios which were independent of high concentrations of soluble CEA. The potency of in vitro lysis was dependent on CEA antigen density but independent of the mutational status in cancer cell lines. Importantly, individual or combinations of mutated KRAS and BRAF oncogenes, activating PI3KCA mutations, loss of PTEN expression, and loss-of-function mutations in TP53 did not reduce the activity in vitro. MEDI-565 also prevented growth of human xenograft tumors which harbored various mutations. These findings suggest that MEDI-565 represents a potential treatment option for patients with CEA positive tumors of diverse origin, including those with individual or combinations of somatic mutations that may be less responsive to chemotherapy and other targeted agents.

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Antitumor activity of MEDI-565 in human tumor xenograft mouse models. (A) Mean tumor volume of Kras and PI3KCA mutant LS174T colon (CEA positive) or HeyA8 ovarian (CEA negative) tumor cells engrafted with human T cells in SCID mice and treated daily with PBS, MEDI-565 or control BiTE® antibody, as indicated (arrows) for 5 days. (B) Activity of MEDI-565 administered by the IV or SC routes of administration in mice engrafted with LS174T cells and human T cells. (C) Mean tumor volume of Kras, BRAF, PI3KCA and/or TP53 mutant tumors (HT-29, H727, HPAC, HPAF II) and wild-type (MKN45) tumors engrafted with human T cells. Error bars represent SEM. Arrows indicate study days when mice were administered test article. *, p < 0.05, Mann-Whitney rank sum test.
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f0005: Antitumor activity of MEDI-565 in human tumor xenograft mouse models. (A) Mean tumor volume of Kras and PI3KCA mutant LS174T colon (CEA positive) or HeyA8 ovarian (CEA negative) tumor cells engrafted with human T cells in SCID mice and treated daily with PBS, MEDI-565 or control BiTE® antibody, as indicated (arrows) for 5 days. (B) Activity of MEDI-565 administered by the IV or SC routes of administration in mice engrafted with LS174T cells and human T cells. (C) Mean tumor volume of Kras, BRAF, PI3KCA and/or TP53 mutant tumors (HT-29, H727, HPAC, HPAF II) and wild-type (MKN45) tumors engrafted with human T cells. Error bars represent SEM. Arrows indicate study days when mice were administered test article. *, p < 0.05, Mann-Whitney rank sum test.

Mentions: The KRAS pathway and TP53 non-mutated gastric cancer line MKN45 and the mutated cell lines LS174T (colon), HT-29 (colon), HPAC (pancreas), HPAF II (pancreas) and H727 (lung) all express CEA and were used to establish xenograft tumor models in immunodeficient SCID mice. In addition, the HeyA8 (ovary) cell line that lacks expression of CEA was used as a control model in the mouse studies. Human T cells were administered to mice in the form of unstimulated PBMCs enriched for CD3+ T cells combined with the respective tumor cells at the indicated ratios before injection. Human PBMCs enriched for CD3+ T cells did not significantly affect the outgrowth of each tumor line in the absence of MEDI-565 (Fig. 5). Similarly, administration of the vehicle alone (PBS) or the control BiTE® antibody construct at 20 μg/dose/mouse for 5 d did not significantly inhibit growth of the human tumor cells in any of the mouse xenograft models. However, the control BiTE® antibody construct did produce noticeable (but not statistically significant) tumor growth reduction in the LS174T model (Fig. 5A and 5B), and may represent a degree of non-specific activity of the anti-CD3 arm of the control BiTE® antibody construct in these experiments.Figure 5.


CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas.

Oberst MD, Fuhrmann S, Mulgrew K, Amann M, Cheng L, Lutterbuese P, Richman L, Coats S, Baeuerle PA, Hammond SA - MAbs (2014)

Antitumor activity of MEDI-565 in human tumor xenograft mouse models. (A) Mean tumor volume of Kras and PI3KCA mutant LS174T colon (CEA positive) or HeyA8 ovarian (CEA negative) tumor cells engrafted with human T cells in SCID mice and treated daily with PBS, MEDI-565 or control BiTE® antibody, as indicated (arrows) for 5 days. (B) Activity of MEDI-565 administered by the IV or SC routes of administration in mice engrafted with LS174T cells and human T cells. (C) Mean tumor volume of Kras, BRAF, PI3KCA and/or TP53 mutant tumors (HT-29, H727, HPAC, HPAF II) and wild-type (MKN45) tumors engrafted with human T cells. Error bars represent SEM. Arrows indicate study days when mice were administered test article. *, p < 0.05, Mann-Whitney rank sum test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4622052&req=5

f0005: Antitumor activity of MEDI-565 in human tumor xenograft mouse models. (A) Mean tumor volume of Kras and PI3KCA mutant LS174T colon (CEA positive) or HeyA8 ovarian (CEA negative) tumor cells engrafted with human T cells in SCID mice and treated daily with PBS, MEDI-565 or control BiTE® antibody, as indicated (arrows) for 5 days. (B) Activity of MEDI-565 administered by the IV or SC routes of administration in mice engrafted with LS174T cells and human T cells. (C) Mean tumor volume of Kras, BRAF, PI3KCA and/or TP53 mutant tumors (HT-29, H727, HPAC, HPAF II) and wild-type (MKN45) tumors engrafted with human T cells. Error bars represent SEM. Arrows indicate study days when mice were administered test article. *, p < 0.05, Mann-Whitney rank sum test.
Mentions: The KRAS pathway and TP53 non-mutated gastric cancer line MKN45 and the mutated cell lines LS174T (colon), HT-29 (colon), HPAC (pancreas), HPAF II (pancreas) and H727 (lung) all express CEA and were used to establish xenograft tumor models in immunodeficient SCID mice. In addition, the HeyA8 (ovary) cell line that lacks expression of CEA was used as a control model in the mouse studies. Human T cells were administered to mice in the form of unstimulated PBMCs enriched for CD3+ T cells combined with the respective tumor cells at the indicated ratios before injection. Human PBMCs enriched for CD3+ T cells did not significantly affect the outgrowth of each tumor line in the absence of MEDI-565 (Fig. 5). Similarly, administration of the vehicle alone (PBS) or the control BiTE® antibody construct at 20 μg/dose/mouse for 5 d did not significantly inhibit growth of the human tumor cells in any of the mouse xenograft models. However, the control BiTE® antibody construct did produce noticeable (but not statistically significant) tumor growth reduction in the LS174T model (Fig. 5A and 5B), and may represent a degree of non-specific activity of the anti-CD3 arm of the control BiTE® antibody construct in these experiments.Figure 5.

Bottom Line: Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome.The potency of in vitro lysis was dependent on CEA antigen density but independent of the mutational status in cancer cell lines.Importantly, individual or combinations of mutated KRAS and BRAF oncogenes, activating PI3KCA mutations, loss of PTEN expression, and loss-of-function mutations in TP53 did not reduce the activity in vitro.

View Article: PubMed Central - PubMed

Affiliation: a MedImmune LLC ; Gaithersburg , MD USA.

ABSTRACT
Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome. Novel therapeutics with mechanisms of action that are independent of mutational status would therefore fulfill a current unmet clinical need. Here the CEA and CD3 bispecific single-chain antibody MEDI-565 (also known as MT111 and AMG 211) was evaluated for its ability to activate T cells both in vitro and in vivo and to kill human tumor cell lines harboring various somatic mutations commonly found in colorectal cancers. MEDI-565 specifically bound to normal and malignant tissues in a CEA-specific manner, and only killed CEA positive cells. The BiTE® antibody construct mediated T cell-directed killing of CEA positive tumor cells within 6 hours, at low effector-to-target ratios which were independent of high concentrations of soluble CEA. The potency of in vitro lysis was dependent on CEA antigen density but independent of the mutational status in cancer cell lines. Importantly, individual or combinations of mutated KRAS and BRAF oncogenes, activating PI3KCA mutations, loss of PTEN expression, and loss-of-function mutations in TP53 did not reduce the activity in vitro. MEDI-565 also prevented growth of human xenograft tumors which harbored various mutations. These findings suggest that MEDI-565 represents a potential treatment option for patients with CEA positive tumors of diverse origin, including those with individual or combinations of somatic mutations that may be less responsive to chemotherapy and other targeted agents.

Show MeSH
Related in: MedlinePlus