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The New Frontier of Antibody Drug Conjugates: Targets, Biology, Chemistry, Payloads

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Abstract

Over a hundred years ago, Dr. Paul Erlich, the famed Nobel Laureate, postulated a “magic bullet theory” for targeted delivery of pharmaceutical agents. Antibody-drug conjugates (ADCs) are one manifestation of that theory and consist of a highly specific tumor-antigen-targeting monoclonal antibody (mAb) that carries a chemically attached toxin for internalization and release within a tumor cell, facilitating its destruction in a precision manner. ADCs represent the interface of three separate scientific advancements: (1) technologies that generate mAbs with extraordinary selectivity and affinity for their targets; (2) improved knowledge of highly potent, cytotoxic natural products; and (3) advancements in synthetic medicinal and bioorganic chemistry. The recent regulatory approvals of two ADCs have provided clinical proof of principle that this therapeutic modality has a role to play in the antitumor armamentarium. This review has two distinct goals. The first is to introduce ADCs in clinical development that we believe represent the best of a new wave of investigational drug candidates in this field. The second is to review and expand upon the technology development that is driving the field forward, using better linker/payload chemistry and improved processes. Finally, we consider the hypothesis that ADCs will not only continue to advance in oncology care, but will in many settings also become standard-of-care therapeutics.

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Abbreviations

ADC:

Antibody-drug conjugate

ALL:

Acute lymphoblastic leukemia

ASH:

American Society of Hematology

BTD:

Breakthrough therapy designation

CLL:

Chronic lymphocytic leukemia

CR:

Complete response

CRi:

CR with incomplete hematologic recovery

DLBCL:

Diffuse large B cell lymphoma

DLT:

Dose-limiting toxicity

DM1:

Derivative of maytansine

DOR:

Duration of response

FL:

Follicular lymphoma

FR:

Folate receptor

FTD:

Fast track designation

IC:

Investigator’s choice

IHC:

Immunohistochemistry

mAb:

Monoclonal antibody

MCC:

[N-maleimidomethyl] cyclohexane-1-carboxylate

MMAE:

Monomethyl auristatin E

MMAF:

Monomethyl auristatin F

MTD:

Maximum tolerated dose

NHL:

Non-Hodgkin lymphoma

ORR:

Objective response rate

OS:

Overall survival

PFS:

Progression-free survival

TNBC:

Triple-negative breast cancer

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Authors and Affiliations

  1. Halozyme Therapeutics, Inc., 11388 Sorrento Valley Road, San Diego, CA, USA

    Christopher D. Thanos

  2. SugarCone Biotech LLC, Holliston, MA, 01746, USA

    Paul D. Rennert

  3. Aleta Biotherapeutics, Natick, MA, 01746, USA

    Paul D. Rennert

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  1. Christopher D. Thanos
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  1. SugarCone Biotech LLC, Holliston, Massachusetts, USA

    Paul D. Rennert

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Thanos, C.D., Rennert, P.D. (2016). The New Frontier of Antibody Drug Conjugates: Targets, Biology, Chemistry, Payloads. In: Rennert, P. (eds) Novel Immunotherapeutic Approaches to the Treatment of Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-29827-6_8

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