Anti-MMAE / F monoclonal antibody (CABT-L3103)

Specifications


Host Species
Mouse
Antibody Isotype
IgG
Clone
C23B3
Species Reactivity
N/A
Conjugate
Unconjugated

Applications


Application Notes
Optimal dilutions for each application to be determined by the researcher. Prepare working dilution immediately before use.
*Suggested working dilutions are given as a guide only. It is recommended that the user titrates the product for use in their own experiment using appropriate negative and positive controls.

Target


Alternative Names
Monomethyl auristatin E; MMAE; Monomethyl auristatin F; MMAF

Citations


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References


Reduction-alkylation strategies for the modification of specific monoclonal antibody disulfides

BIOCONJUGATE CHEMISTRY

Authors: Sun, MMC; Beam, KS; Cerveny, CG; Hamblett, KJ; Blackmore, RS; Torgov, MY; Handley, FGM; Ihle, NC; Senter, PD; Alley, SC

Site-specific conjugation of small molecules and enzymes to monoclonal antibodies has broad utility in the formation of conjugates for therapeutic, diagnostic, or structural applications. Precise control over the location of conjugation would yield highly homogeneous materials that could have improved biological properties. We describe for the first time chemical reduction and oxidation methods that lead to preferential cleavage of particular monoclonal antibody interchain disulfides using the antiCD-30 IgG1 monoclonal antibody eAC10. Alkylation of the resulting cAC10 cysteine thiols with the potent antimitotic agent monomethyl auristatin E (MMAE) enabled the assignment of drug conjugation location by purification with hydrophobic interaction chromatography followed by analysis using reversed-phase HPLC and capillary electrophoresis. These analytical methods demonstrated that treating cAC10 with reducing agents such as DTT caused preferential reduction of heavy-light chain disulfides, while reoxidation of fully reduced cAC10 interchain disulfides caused preferential reformation of heavy-light chain disulfides. Following MMAE conjugation, the resulting conjugates had isomeric homogeneity as high as 60-90%, allowing for control of the distribution of molecular species. The resulting conjugates are highly active both in vitro and in vivo and are well tolerated at efficacious doses.

Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for THIOMAB (TM) Drug Conjugates

PHARMACEUTICAL RESEARCH

Authors: Sukumaran, Siddharth; Gadkar, Kapil; Zhang, Crystal; Bhakta, Sunil; Liu, Luna; Xu, Keyang; Raab, Helga; Yu, Shang-Fan; Mai, Elaine; Fourie-O'Donohue, Aimee; Kozak, Katherine R.; Ramanujan, Saroja; Junutula, Jagath R.; Lin, Kedan

THIOMAB (TM) drug conjugates (TDCs) with engineered cysteine residues allow site-specific drug conjugation and defined Drug-to-Antibody Ratios (DAR). In order to help elucidate the impact of drug-loading, conjugation site, and subsequent deconjugation on pharmacokinetics and efficacy, we have developed an integrated mathematical model to mechanistically characterize pharmacokinetic behavior and preclinical efficacy of MMAE conjugated TDCs with different DARs. General applicability of the model structure was evaluated with two different TDCs. Pharmacokinetics studies were conducted for unconjugated antibody and purified TDCs with DAR-1, 2 and 4 for trastuzumab TDC and Anti-STEAP1 TDC in mice. Total antibody concentrations and individual DAR fractions were measured. Efficacy studies were performed in tumor-bearing mice. An integrated model consisting of distinct DAR species (DAR0-4), each described by a two-compartment model was able to capture the experimental data well. Time series measurements of each Individual DAR species allowed for the incorporation of site-specific drug loss through deconjugation and the results suggest a higher deconjugation rate from heavy chain site HC-A114C than the light chain site LC-V205C. Total antibody concentrations showed multi-exponential decline, with a higher clearance associated with higher DAR species. The experimentally observed effects of TDC on tumor growth kinetics were successfully described by linking pharmacokinetic profiles to DAR-dependent killing of tumor cells. Results from the integrated model evaluated with two different TDCs highlight the impact of DAR and site of conjugation on pharmacokinetics and efficacy. The model can be used to guide future drug optimization and in-vivo studies.

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