Introduction
Therapeutic monoclonal antibodies - a view from above
Generic name | Proprietary name | Target | Technology | Isotype | Additional manipulations | Year FDA approved | Approved clinical indication |
---|---|---|---|---|---|---|---|
Rituximab | Rituxin®/ Mabthera® | CD20 | Mouse Hybridoma | IgG1-kappa | Chimeric | 1997 | NHL; later CD20+CLL, FL, RA |
Transtuzumab | Herceptin® | HER-2 | Mouse Hybridoma | IgG1-kappa | Humanized | 1998 | HER-2+ MBC |
Alemtuzumab | Campath®/ Mabcampath® | CD52 | Rat Hybridoma | IgG1-kappa | Humanized | 2001 | CL L, T-cellLymphoma |
Ibritomomab tiuxitan | Zevalin® | CD20 | Mouse monoclonal | IgG1-kappa | Conjugated to Yittrium-90 | 2002 | NHL |
Tositumomab | Bexxar® | CD20 | Mouse monoclonal | IgG2a-lambda | Conjugated to I-131 | 2003 | NHL |
Cetuximab | Erbitux® | EGRF, HER-1 | Mouse monoclonal | IgG1- kappa | Chimeric | 2004 | EGRF+ MCC |
Bevacizumab | Avastin® | VEGF | Mouse monoclonal | IgG1- kappa | Humanized | 2004 | MCC |
Panitumumab | Vectibix™ | EGRF, HER-1 | Human monoclonal | IgG2-kappa | Human | 2006 | MCC |
Ofatumumab | Arzerra™ | CD20 | Human monoclonal | IgG1-kappa | Human | 2009 | Refractory CLL |
Ipilimumab | Yervoy™ | CTLA-4 | Human monoclonal | IgG1-kappa | Human | 2011 | MMel |
Pertuzumab | Perjeta™ | EGFR2, HER-2 | Mouse monoclonal | IgG1-kappa | Humanized | 2012 | BC |
TMAs for hematological cancer
Rituxin
Anti-CD20-radioisotope conjugates
Newer anti-CD20 TMAs
Ofatumumab
Veltuzumab
Ocrelizumab
Next-generation anti-CD20 antibodies
Targets other than CD-20
Alemtuzumab
Milatuzumab
Antibody drug conjugates (ADCs)
Generic name | Trade/code name | Target | Antibody source | Antibody isotype | Other manipulations | Conjugated to: | Clinical status | Indication |
---|---|---|---|---|---|---|---|---|
Gemtuzumab ozogamicin | Mylotag® | CD33 | Mouse monoclonal | IgG4- kappa | Humanized | Calicheamicin | Approved 2000 WITHDRAWN 2010 | CD33+AML |
Brentuximab vedotin | Adcentris™ | CD30 (TNFR) | Mouse monoclonal | IgG1- kappa | Chimeric | Monomethyl auristatin E (MMAE) | Approved 2011 | HL |
Trastuzumab emtansine | MCC-DM1/ T-DM1 | HER-2 | Mouse monoclonal | IgG1- kappa | Humanized | Maytansinoid DM1 | Phase III | HER-2+ MBC |
Inotuzumab ozogamicin | CMC-544 | CD22 | Mouse monoclonal | IgG4- kappa | Humanized | Calicheamicin | Phase III Phase II | NHL DLBCL |
Lorvotuzumab mertansine | IMGN901 | CD56 | Mouse monoclonal | IgG1- kappa | Humanized | Maytansinoid DM1 | Orphan Drug 2010; Phase II | SMLC, OC, MM |
------ | SAR3419 | CD19 | Mouse monoclonal | IgG1 | Humanized | Maytasinoid DM4 | Phase I | NHL |
Gemtuzumab ozogamicin (Mylotag)
Brentuximab vedotin (Adcetris)
Trastuzumab emtansine (T-DM1)
Inotuzumab ozogamicin (CMC-544)
Lorvotuzumab mertansine (IMGN901)
SAR3419
Limitations of Abs as drug carriers
Item | Antibodies (full length) | Peptides |
---|---|---|
Discovery of novel cell surface targets
| Most approved TMAs do not target TSAs; for traditional mAbs target must be antigenic; screening selects mAbs to dominant epitopes; mAb specs depend on strain mouse/rat used | Target does not need to be antigenic; no prior knowledge of target molecule needed |
Generation technology
| Traditionally via murine hybridoma, then humanization; humanized mouse; via phage scFv phage display then grafting to Ig backbone | Combinatorial DNA, RNA, peptide library phage or cell based display technologies (random or scFv based); Combinatorial chemistry |
Molecular structure
| Standard Ab unit; different Ig isotypes; bispecific Ab; multi-bodies | Linear; cyclic; scFv; non natural amino acids; novel small molecules |
Intracellular transport
| Not a selection criteria of currently approved TMAs; technically difficult to select during screening | Screening technologies allow for easy selection of candidates that induce rapid endocytosis |
Pharmacodynamics and Pharmacokinetics
| Non-linear, depends of many variables, difficult to predict | Smaller molecular mass; larger formulation knowledge base for designed PD and PK |
Conjugation of carrier to drug (for ADC or PDC) | Only ~50% mAb bound to drug; difficult to predict mAb/drug stoichiometry and drug position; conjugation chemistry limited to aqueous solutions. | Enhanced flexibility in conjugation chemistry for coupling to linker and drug, allowing wider selection of drugs including non-water soluble compounds, synthesis in organic solvents and aqueous solutions ; scaffolds available for conjugation to different drugs; formation of metal complexes; defined and predictable products; |
Antigenicity of final product
| Depends of extent of humanization. | Negligible |
Bystander immune effector function
| ADCC; CDC; CTL?; | None |
Tumor penetration
| Limited in solid tumors | Enhanced |
Manufacture/Quality Control | Structure of ADC heterogeneous; high upstream development, cell culture, bioreactor design) and downstream ( purification) costs | Significantly lower production costs (up to ~35 amino acids); increased product reproducibility |