Anti-proliferative compounds and bispecific antibodies against BCMA and CD3 for combined use
A bispecific antibody and compound technology, applied in the direction of antibodies, drug combinations, antibody medical components, etc., can solve problems such as disease recurrence
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Embodiment 1
[0501] Example 1: 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methanol yl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (compound 1).
[0502]
[0503] 2-Amino-5-methoxy-5-oxopentanoic acid. To a suspension of 2-aminoglutaric acid (250 g, 1.70 mol) in dry methanol (2.5 L) was added trimethylchlorosilane (277 g, 2.55 mol) under nitrogen over 30 minutes. The resulting clear solution was stirred at room temperature (20° C.) for 30 minutes. 1H NMR showed complete consumption of starting material. The reaction mixture was used in the next step without further work-up. 1 H NMR: 400MHz CD 3 ODδ: 4.17-4.15 (m, 1H), 3.71 (s, 3H), 2.70-2.60 (m, 2H), 2.33-2.25 (m, 2H).
[0504] 2-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid. To the above solution was added triethylamine (275 g, 2.72 mol) and di-tert-butyl dicarbonate (447.35 g, 2.05 mol). The reaction mixture was stirred at 25°C for 2 hours. The solution was concentrated to dryness, then water ...
Embodiment 2
[0515] Example 2: (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl) Synthesis of oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (compound 2).
[0516]
[0517] (4S)-5-Amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoic acid tert-butyl ester. To a solution of (2S)-2-(benzyloxycarbonylamino)-5-tert-butoxy-5-oxo-pentanoic acid (150 g, 445 mmol) in 1,4-dioxane (1.50 L) was added Di-tert-butyl dicarbonate (155 g, 711 mmol), pyridine (70.3 g, 889 mmol) and ammonium bicarbonate (105 g, 1.33 mol). The reaction mixture was stirred at 18°C for 16 hours, then concentrated. The residue was dissolved in ethyl acetate (5.0 L) and water (5.0 L), the organic layer was separated and washed with HCl (3.0 mL, 1 N), saturated sodium bicarbonate (3.0 L), brine (3.0 L), and washed with Drying over anhydrous sodium sulfate, filtration and concentration afforded crude tert-butyl (4S)-5-amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoate (450 g, crude) as a white solid, It ...
Embodiment 3
[0527] Example 3: Anti-CD3 Antibody
[0528] Preferably, the anti-CD3 antibody comprises a variable domain VH comprising the heavy chain CDRs of SEQ ID NO: 1, 2 and 3 as heavy chain CDR1, CDR2 and CDR3, respectively; and variable Domain VL comprising the light chain CDRs of SEQ ID NO: 4, 5 and 6 as light chain CDR1, CDR2 and CDR3, respectively. Preferably, the antibody comprises the variable domains of SEQ ID NO: 7 (VH) and SEQ ID NO: 8 (VL). Anti-CD3 antibodies as described above were used to generate T cell bispecific antibodies according to the following examples.
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