A system for sequencing one or more variable portions of an unknown monoclonal antibody, mAb, comprising: a genome database for homology search; a separation device, an ion source device; a mass spectrometer that includes a dissociation device and a mass analyzer; and a processor configured to instruct the separation device to separate an unknown intact mAb or reduced mAb subunits of a known mAb class from a sample, to instruct the ion source device to ionize the unknown intact mAb or reduced mAb subunits, to instruct the mass spectrometer to fragment the ionized unknown intact mAb or reduced mAb subunits using the dissociation device and to mass analyze resulting product ions using the mass analyzer, producing one or more product ion spectra (644, 1130), to calculate theoretical product ion peaks for one or more constant portions of the known mAb class, to remove the calculated theoretical product ion peaks from the one or more product ion spectra, producing one or more difference product ion spectra (652, 1150), to apply de novo sequencing to the one or more difference product ion spectra, by assigning one or more amino acid sequences to the product ions in the one or more difference product ion spectra to produce one or more candidate sequences for one or more variable portions of the unknown intact mAb or reduced mAb subunits, and to search the genome database for matches to the one or more candidate sequences, producing one or more matched sequences for the one or more variable portions. a genome database for homology search; a separation device, an ion source device; a mass spectrometer that includes a dissociation device and a mass analyzer; and a processor configured to instruct the separation device to separate an unknown intact mAb or reduced mAb subunits of a known mAb class from a sample, to instruct the ion source device to ionize the unknown intact mAb or reduced mAb subunits, to instruct the mass spectrometer to fragment the ionized unknown intact mAb or reduced mAb subunits using the dissociation device and to mass analyze resulting product ions using the mass analyzer, producing one or more product ion spectra (644, 1130), to calculate theoretical product ion peaks for one or more constant portions of the known mAb class, to remove the calculated theoretical product ion peaks from the one or more product ion spectra, producing one or more difference product ion spectra (652, 1150), to apply de novo sequencing to the one or more difference product ion spectra, by assigning one or more amino acid sequences to the product ions in the one or more difference product ion spectra to produce one or more candidate sequences for one or more variable portions of the unknown intact mAb or reduced mAb subunits, and to search the genome database for matches to the one or more candidate sequences, producing one or more matched sequences for the one or more variable portions. to instruct the separation device to separate an unknown intact mAb or reduced mAb subunits of a known mAb class from a sample, to instruct the ion source device to ionize the unknown intact mAb or reduced mAb subunits, to instruct the mass spectrometer to fragment the ionized unknown intact mAb or reduced mAb subunits using the dissociation device and to mass analyze resulting product ions using the mass analyzer, producing one or more product ion spectra (644, 1130), to calculate theoretical product ion peaks for one or more constant portions of the known mAb class, to remove the calculated theoretical product ion peaks from the one or more product ion spectra, producing one or more difference product ion spectra (652, 1150), to apply de novo sequencing to the one or more difference product ion spectra, by assigning one or more amino acid sequences to the product ions in the one or more difference product ion spectra to produce one or more candidate sequences for one or more variable portions of the unknown intact mAb or reduced mAb subunits, and to search the genome database for matches to the one or more candidate sequences, producing one or more matched sequences for the one or more variable portions.