Moore et al. identified gpA33 as a target found on colorectal cancer stem cell lines as well as on primary and metastatic colorectal tumor specimens, and describe preclinical analyses supporting the clinical development of a gpA33 T cell re-directing antibody. The dual-affinity retargeting (DART) molecule used a three-chain platform design, including a half-life-extending Fc region, and demonstrated efficient colorectal cancer cell lysis in vitro and in vivo. Multiple T cell subsets (CD8+, CD4+, and CD4+FOXP3+ Treg) were active in cytolysis. Prolonged antigen exposure drove expansion and loss of cytokine production, but cytolytic activity was retained.

We have developed MGD007 (anti-glycoprotein A33 x anti-CD3), a DART(R) protein designed to redirect T-cells to target gpA33 expressing colon cancer. The gpA33 target was selected based on an antibody-based screen to identify cancer antigens universally expressed in both primary and metastatic CRC specimens, including putative cancer stem cell populations. MGD007 displays the anticipated bispecific binding properties and mediates potent lysis of gpA33-positive cancer cell lines, including models of colorectal cancer stem cells, through recruitment of T-cells. Xenograft studies showed tumor growth inhibition at doses as low as 4 microg/kg. Both CD8 and CD4 T cells mediated lysis of gpA33-expressing tumor cells, with activity accompanied by increases in granzyme and perforin. Notably, suppressive T-cell populations could also be leveraged to mediate lysis of gpA33 expressing tumor cells. Concomitant with CTL activity, both T-cell activation and expansion are observed in a gpA33-dependent manner. No cytokine activation was observed with human PBMC alone, consistent with the absence of gpA33 expression on peripheral blood cell populations. Following prolonged exposure to MGD007 and gpA33 positive tumor cells, T cells express PD 1 and LAG-3 and acquire a memory phenotype but retain ability to support potent cell killing. In cynomolgus monkeys, 4 weekly doses of 100 microg/kg were well tolerated, with prolonged PK consistent with that of an Fc-containing molecule. Taken together MGD007 displays potent activity against colorectal cancer cells consistent with a mechanism of action endowed in its design and support further investigation of MGD007 as a potential novel therapeutic treatment for colorectal cancer.

Author Info: (1) MacroGenics, Inc. moorep@macrogenics.com. (2) MacroGenics, Inc. (3) MacroGenics, Inc. (4) MacroGenics, Inc. (5) Cell Biology, CanFel Therapeutics LLC. (6) MacroGenics, Inc. (7) MacroGenics, Inc

Author Info: (1) MacroGenics, Inc. moorep@macrogenics.com. (2) MacroGenics, Inc. (3) MacroGenics, Inc. (4) MacroGenics, Inc. (5) Cell Biology, CanFel Therapeutics LLC. (6) MacroGenics, Inc. (7) MacroGenics, Inc. (8) MacroGenics, Inc. (9) MacroGenics, Inc. (10) MacroGenics, Inc. (11) MacroGenics, Inc. (12) MacroGenics, Inc. (13) MacroGenics, Inc. (14) MacroGenics, Inc. (15) MacroGenics, Inc. (16) MacroGenics, Inc. (17) MacroGenics, Inc. (18) MacroGenics, Inc. (19) MacroGenics, Inc. (20) MacroGenics, Inc. (21) MacroGenics, Inc. (22) MacroGenics, Inc. (23) MacroGenics, Inc. (24) MacroGenics, Inc. (25) MacroGenics, Inc. (26) MacroGenics, Inc. (27) MacroGenics, Inc. (28) MacroGenics, Inc. (29) MacroGenics, Inc.

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