Treatment of cancer with her2xcd3 bispecific antibodies in combination with Anti-her2 mab
An antibody and cancer technology, applied in the direction of antibody medical components, antibodies, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc.
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example 1
[0231] Example 1. Preclinical Efficacy of BTRC4017A and Trastuzumab Co-Treatment
[0232] A full-length, IgG1 TDB, BTRC4017A that binds both HER2 and CD3 was engineered using "knob and socket" (see, e.g., U.S. Pat. No. 5,731,168) and has an anti-HER2 arm that includes the 4D5 HER2 binding site and includes the 40G5c CD3 Anti-CD3 arm of the binding site (see, eg, WO 2015 / 095392). The 4D5 HER2 binding site of BTRC4017A is derived from trastuzumab and binds the same epitope in domain IV of HER2, as figure 1 shown. Trastuzumab competes with BTRC4017A for binding to HER2 and thus may interfere with BTRC4017A activity.
[0233] In vitro pharmacology of BTRC4017A combined with trastuzumab (Herceptin)
[0234] The effect of trastuzumab on BTRC4017A activity was tested in vitro and in vivo using a HER2-amplified KPL4 cell line, which represents HER2-positive cancers. The effect of this combination was also modeled using the HT55 cell line, which expresses low levels of HER2, si...
example 2
[0242] Example 2. Dose-fractionated, dose-escalating dosing regimen for HER2-positive cancers using BTRC4017A and trastuzumab
[0243] To mitigate potential cytokine-driven toxicity, BTRC4017A was administered in cycle 1 (C1) in a dose-split regimen in which the first dose was less than the second dose. In a two-step dose-split regimen, the second dose in C1 is less than the third dose. Cycle 2 and any necessary subsequent cycles involved a single administration of a BTRC4017A dose equivalent to the maximum dose of BTRC4017A in C1.
[0244] Trastuzumab was administered on day -1 of C1 to properly differentiate any infusion-related reactions (IRRs) that could be associated with BTRC4017A versus trastuzumab. All subsequent trastuzumab doses in cycle 2 (C2) and beyond were administered on cycle day 1, prior to BTRC4017A administration. A summary of the trastuzumab administration schedule is provided in Table 4 below:
[0245] Table 4: Trastuzumab infusion time and observation ...
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