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                                                                  EXHIBIT 10.12

                              CONSULTING AGREEMENT

     This Consulting Agreement (the "Agreement") is made and effective as of
this 1st day of March, 2003, by and between HYBRIDON, INC., a Delaware
corporation with its principal place of business at 345 Vassar Street,
Cambridge, Massachusetts 02139 ("Hybridon", the "Company"), and Paul C.
Zamecnik, residing at 101 Chestnut Street, Boston, Massachusetts 02108 (the
"Consultant").

In consideration of the mutual promises contained herein and other good and
valuable consideration, the receipt and sufficiency of which is acknowledged,
the parties agree as follows:

1. SERVICES. The Consultant agrees during the Consulting Period (as defined
below) to perform such consulting, advisory, and related services to and for
Hybridon as the Company may reasonably request from time to time. The Consultant
agrees to deliver such services either in person (at the facilities of Hybridon
or such other locations reasonably acceptable to both Hybridon and the
Consultant) or by other telephonic or electronic media or means, as Hybridon may
reasonably request for the term of this Agreement.

Any and all consultation services provided by the Consultant to Hybridon under
this Agreement shall be priorly approved by Hybridon. "Prior approval" under
this Agreement shall mean those consultation services that may be reasonably
requested or communicated by Hybridon to the Consultant via any agreed upon
telephonic or electronic media or means, whether oral or written.

2. TERM. The term of this Agreement (the "Consulting Period") shall commence on
the effective date of this Agreement and shall end on February 28, 2005, or upon
termination by either party, with or without cause in his or its sole
discretion, upon 60 days' prior written notice to the other party. The
provisions of Sections 4 and 5 hereof shall survive the expiration or
termination of this Agreement.

3. COMPENSATION. In exchange for the Services provided by the Consultant under
Section 1, herein above, Hybridon shall pay to the Consultant a consulting fee
of $20,000 (twenty thousand dollars) per year for general consulting services,
provided by the Consultant from time to time at the Company's request, such fee
to be paid annually in arrears in cash or in an amount of the Company's common
stock of equivalent value based on the market price.

In addition, Hybridon shall reimburse the Consultant for all reasonable and
necessary expenses incurred or paid by the Consultant in connection with the
performance of such services with the prior approval of Hybridon, including, but
not limited to, travel expenditures expended by the Consultant in the
performance of consultation services under this Agreement, provided the
Consultant shall submit an expense report to Hybridon as the expenses are
incurred. The Consultant shall not be entitled to any benefits, coverages, or
privileges, including those made available to the employees of Hybridon.

4. CONFIDENTIALITY AND ASSIGNMENT OF INVENTIONS. The Consultant acknowledges
that he has on or prior to the date of this agreement, executed and delivered to
Hybridon an Invention and

                                                                          Page 1

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Non-Disclosure Agreement (the "Confidentiality Agreement"), incorporated
into the present Agreement here in SCHEDULE A attached. The Consultant hereby
affirms and ratifies the obligations thereunder. The Consultant represents that
his retention as a consultant with Hybridon and his performance under this
Agreement does not, and shall not, breach any agreement that obligates him to
keep in confidence any trade secrets or confidential or proprietary information
of his or of any other party or to refrain from competing, directly or
indirectly, with the business of any other party. The Consultant shall not
disclose to Hybridon any trade secrets or confidential or proprietary
information of any other party.

5.       NONCOMPETITION AND BREACH.

(a)      The provisions of this Agreement including the executed Confidential
         Disclosure Agreement at SCHEDULE A, attached hereto, are necessary for
         the protection of the business and goodwill of Hybridon and are
         considered by the Consultant to be reasonable for such purpose. The
         Consultant agrees that any breach of this Agreement, especially with
         regard to the disclosure of strategies, technologies and/or
         information, proprietary or otherwise, to third parties unrelated to
         this Agreement will cause Hybridon substantial harm and, therefore, in
         the event of any such breach, in addition to other remedies which may
         be available, Hybridon shall have the right to seek specific
         performance and other injunctive and equitable relief.

(b)      If any restriction set forth in this Section 5 is found by any court of
         competent jurisdiction to be unenforceable because it extends for too
         long a period of time, over too great a range of activities, in too
         broad a geographic area, or for any other reason, it shall be
         interpreted to extend only to the maximum extent, whether period of
         time, range of activities, geographic area or other term, as to which
         it may be enforceable.

6. NOTICES. All notices required or permitted under this Agreement shall be in
writing and shall be deemed effective upon personal delivery or upon deposit in
the United States Post Office, by registered or certified mail, postage prepaid,
addressed to the other party at the address shown above, or at such other
address or addresses as either party shall designate to the other in accordance
with this Section 6.

7. ENTIRE AGREEMENT. This Agreement, including SCHEDULE A, shall constitute the
entire agreement between the parties with respect to, and supersede all prior
agreements and understandings, whether written or oral, relating to, the subject
matter of this Agreement.

8. GOVERNING LAW. This Agreement shall be construed, interpreted and enforced in
accordance with the laws of the Commonwealth of Massachusetts, without giving
effect to conflict of laws provisions.

9. SUCCESSORS AND ASSIGNS. This Agreement shall be binding upon, and inure to
the benefit of, both parties and their respective successors and assigns,
including any corporation with which, or into which, Hybridon may be merged or
which may succeed to any part of its assets or business; provided, however, that
the obligations of the Consultant are personal and shall not be assigned by him.

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         IN WITNESS WHEREOF, the parties hereto have executed this Agreement as
of the day and year set forth above.

HYBRIDON, INC.                               CONSULTANT

    /s/ Robert G. Andersen                     /s/ Paul G. Zamecnik
By: ______________________                 By: ____________________

Name:  Robert G. Andersen                  Name: Paul C. Zamecnik, M.D.

Title: CFO and V.P. Operations             SSN:  ###-##-####

                                                                          Page 3

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                                   SCHEDULE A

[Attach executed Confidential Disclosure Agreement prior to execution]

                                                                          Page 4<PAGE>
                                                                   EXHIBIT 10.42

STEPHEN R. SEILER                                           Phone:  617-679-5512
Chief Executive Officer                                       Fax:  617-679-5542
                                                    e-mail: sseiler@hybridon.com
                                                            --------------------

                                                                 August 14, 2002

Isis Pharmaceuticals, Inc.
2292 Faraday Avenue
Carlsbad, California 92008

     Re:      Collaboration and License Agreement; Master Agreement
              -----------------------------------------------------

Gentlemen:

     Reference is hereby made to the Collaboration and License Agreement dated
as of May 24, 2001 (the "Collaboration and License Agreement") by and between
Isis Pharmaceuticals, Inc. ("Isis") and Hybridon, Inc. ("Hybridon") and the
Master Agreement dated as of May 24, 2001 by and between Isis and Hybridon (the
"Master Agreement" and together with the Collaboration and License Agreement,
the "Agreements"). All capitalized terms used herein but not otherwise defined
shall have the meanings set forth in the Agreements.

     Hybridon and Isis hereby agree as follows with respect to the Agreements:

     1. Hybridon shall have no obligation under Section 2.2 of the Master
Agreement to issue any shares of its common stock or make any cash payments to
Isis as a Hybridon Tranche Payment with respect to the second and third Hybridon
Tranche Periods or otherwise.

     2. Isis shall have no obligation under Section 2.3 of the Master Agreement
to issue any shares of its common stock or make any cash payments to Hybridon as
an Isis Tranche Payment with respect to the fourth Isis Tranche Period or
otherwise.

     3. Article V of the the Collaboration and License Agreement shall be
amended for clarification purposes in the manner set forth on Exhibit A attached
to this letter.

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Isis Pharmaceuticals, Inc.
August 14, 2002
Page 2

     In all other respects, the Agreements and the provisions thereof shall
remain in full force and effect.

     If Isis is in agreement with the foregoing, please so indicate by signing
this letter in the space provided below and returning a fully executed copy to
me.

                                                     Very truly yours,

                                                     HYBRIDON, INC.

                                                     /s/ Stephen Seiler
                                                     ------------------

                                                     Stephen Seiler
                                                     Chief Executive Officer

Agreed as of this 14th
Day of August, 2002

ISIS PHARMACEUTICALS, INC.

By: B. Lynne Parshall
    ---------------------

Title:  Executive Vice President
        ------------------------

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                                    EXHIBIT A
                                    ---------

     Article V of the Collaboration and License Agreement shall be deleted in
its entirety and the following shall be inserted in lieu thereof:

                                    ARTICLE V

                                  COLLABORATION
                                  -------------

     In addition to the collaboration between the Parties with respect to
intellectual property protection under Article VI, the Parties shall further
collaborate hereunder through a committee (the "Collaboration Committee")
consisting of two representatives of each Party. The Parties shall establish the
Collaboration Committee within thirty (30) days after the Effective Date. The
Collaboration Committee shall meet at least twice each calendar year in person
or by video conference during the term of this Agreement to review the progress
of Isis' development efforts with respect to Isis' Antisense Products that are
covered by Hybridon Intellectual Property. The Parties intend that the
Collaboration Committee shall act as a forum for the Parties to work
cooperatively to seek to enhance the development of Isis' Antisense Products
that are covered by Hybridon Intellectual Property, including to discuss
scientific and technical matters relating to the development of Isis' Antisense
Products that are covered by Hybridon Intellectual Property, regulatory matters
relating to Isis' Antisense Products that are covered by Hybridon Intellectual
Property and ongoing research and development in the antisense field being
conducted by third parties. Neither Party shall be obligated to disclose any
Confidential Information to the Collaboration Committee. In addition, under no
circumstances shall either Party be obligated to undertake any action as a
result of such Collaboration Committee meetings that would cause either Party to
incur any financial obligation beyond that necessary to cause such Collaboration
Committee meetings to take place in the manner and frequency noted above unless
both Parties agree to such action in writing.

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